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Volume 1 April

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2015

-The Informed Prescriber

N1

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o

H.pylori eradication
may shorten life span
CONTENTS （April 2015,Vol. 1, No. 1）
Editorial:
An independent drug bulletin for medical practice
New Products
SGLT-2 inhibitors:
Unacceptable products -- can we call these “medicines”?

Methadone (Limited use):
Useful only in opioid rotation with special precautions

p.2

p.3

p.5

Reviews
H.pylori eradication may shorten life span:

p.7

Harm of HPV vaccine:

p.9

Gastric cancer risk decreases, but incidence of C.difficile
infection and pneumonia increase instead

Latest information and examination of epidemiological studies

Plain Language Summary
SGLT-2 inhibitors: inaccurate to call these “medicines”

p.13

What is diabetes? What is insulin? What is the target of treatment?

"Pylori" bacteria removal may shorten life
Harm of HPV vaccine: epidemiologic studies do not prove safety

MED CHECK - TIP APRIL 2015 / Vol.1 No.1 ・ Page 

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Editorial

An independent drug bulletin for medical practiceTranslated from the original editorial in the Japanese edition of Med Check-TIP #57 (Jan 2015)

New drugs with new modes of action are continu-

in January 2015 as a single drug bulletin integrating

ously being developed. Most of the current biggest-

the two abovementioned bulletins. Although aimed

selling pharmaceutical products have been marketed inprimarily at professionals, we endeavour to produce

the last 20 years. If these drugs actually benefit health,articles that can be understood by people and the media.

they will be good for people. However, the development

We will take a critical look at new products and withof drugs which prolong life and/or improve patients'

critical evaluation. We will show some of the drugs

quality of life (QOL) has been rare since 1990.

essential to medical practice. Metronidazole (issue #57)

Sometimes, pharmaceutical companies may distortand methadone (# 58) are two examples.

preclinical and clinical data of their products to

Valuable information that cannot be obtained frommake them appear attractive. The Diovan scandal in

any other source will be provided in the new bulletin

which data was falsified is just the tip of the iceberg.

"Med Check-TIP". Despite criticizing substandard

In the case of Tamiflu, Iressa, HPV vaccine andproducts for the past 30 years, we have never been

Actos (pioglitazone), the pharmaceutical companies

sued by a pharmaceutical company. This is because

manipulated data to show these drugs are effective andwe concientiously and thoroughly investigate thesafe. Since the advent of the 21st century, this type ofevidence of efficacy and harm by assessing clinicaldata manipulation has become more common. SGLT-2

evidence as well as animal experiments including

inhibitors are such a type of drug developed andtoxicity studies and epidemiological studies. Whenintroduced in medical practice based on questionable

we notice that important data is unpublished, we ask

efficacy and safety data. Financial incentives from thethe pharmaceutical companies to disclose the data andpharmaceutical industry have influenced the evaluation

have it analyzed independently. The Tamiflu case is oneof medicines by such parties as the researchers (orsuch example, where we have uncovered evidence of

medical societies/associations), regulators, public

increased brain toxicity.

organizations including World Health Organization(http://doi.wiley.com/10.1002/14651858.CD008965.pub4)(WHO), the media and medical journals.

Policy makers and regulatory authorities should be

The role of drug bulletins in Japan is very important,obligated to disclose drug approval dossiers to protect

as prescribers and public alike are inundated by a flood

public health, as demanded by the Cochrane statement.

of information which is often heavily influenced andhttp://www.cochranelibrary.com/editorial/10.1002/14651858.

distorted by the pharmaceutical industry. "The Informed

ED000035

Prescriber" (TIP: founded in 1986) for professionals and"Med Check, Save Lives" (founded in 2001) targetting

We provide information that is completely independent of the pharmaceutical industry.

general public have provided evidence based rational

It is important for the bulletin to be read by as many

information which meets the needs of professionals andpeople as possible in order to improve medical practices

the general public. This is possible, because they arefor the common good. We welcome feedback fromcompletely independent: i.e. free from advertisement,

readers, as it can improve the bulletin qualitatively andfunding or any other assistance from industry.

quantitatively.

The Japanese edition of this bulletin "Med Check The Informed Prescriber" or "Med Check-TIP" started

Page  ・ MED CHECK - TIP APRIL 2015 / Vol.1 No.1

We need your help and support in spreading the wordon our bulletin "Med Check-TIP".

New Products
SGLT-2 inhibitors:
Unacceptable products -- can we call these “medicines”?
Why such toxic agents are touted as “medicines"? Excerpted from Med Check TIP 2015; 15 (#57); pp. 3-7.
Various concerns were expressed before approval. Excerpted from Med Check TIP 2015; 15 (#58); pp. 35-36.

ipragliflozin, tofogliflozin, tabaglyflozin, luseogliflozin, canagliflozin and empagliflozin
Introduction
Six new hypoglycemic agents in one class of product,
SGLT-2 inhibitors were marketed with buzzwords like “newmechanism of action” in recent one year (between April 2014
and February 2015) in Japan. The endpoint of agents whichtarget chronic diseases such as diabetes mellitus must be“prolongation of life” and/or improvement in “quality of life
(QOL)” (Table 1[1] ) .
However, like other hypoglycemic agents, SGLT-2 inhibitors
were not adequately endpoint tested before approval but
merely by indirect surrogate endpoints such as “reductionof fasting glucose level” and “reduction or of "per centglycosylated hemoglobin (HbA1c).” [2-6] Even disease
specific incidence and/or mortality due to such complications
as cardiovascular and/or cerebrovascular incidence/mortality were not investigated among patients in long term
randomized controlled trials.
The mechanism of action of SGLT-2 inhibitors is thelowering of blood glucose level by inhibiting glucose
reabsorption via renal tubules and by excreting glucose
through urine. They do not lead to the improvement of
glucose metabolism but only act to lower blood glucose level.
Leading Japanese diabetologists warned the public of
the harmful effects of SGLT-2 inhibitors, not once but
twice soon after marketing: saying "Harmful effects of
SGLT-2 inhibitors that we were concerned about became
reality."[7] The concerns with SGLT-2 inhibitors included(1) serious hypoglycemia, (2) dehydration, (3) ketoacidosis,(4) thromboembolism including cerebrovascular diseases,(5) urinary tract/genital infections, (6) serious cutaneouscomplications such as Stevens-Jonson syndrome.
Abstract of Med Check TIP 2015; 15 (#57); pp. 3-7.
These clinical problems that were revealed just after
the marketing of SGLT-2 inhibitors, but which were easily
predictable in the preclinical stage of these products included:1) that SGLT-2 receptors exist not only in renal tubule cells,
but in virtually all cells, e.g. the central nervous system[8,9].
2) Even if SGLT-2 inhibitors selectively inhibit SGLT-2
receptors, a high concentration of SGLT-2 inhibitors in theintestinal tract may also inhibit SGLT-1 receptors in theintestines.
3) Non-observable adverse effect level (NOAEL) was not“Med Check” #44 and #45 (currently only available in Japanese)
provide more information on principles of diabetes treatment
including the assessment of diabetic drugs other than SGLT-2
inhibitors. A condensed version can be found under “Plain
Language Summary” on p.13.

Table 1. Strength of endpoints(ranked in descending order) [1]
A.Total mortality (or overall survival)
Comment: the most important and is the most easily defined andleast subject to investigator bias.
B-1. Cause-specific mortality
Comment: more subjective than total mortality, more subject toinvestigator bias in its determination. It may also miss important
effects of therapy that actually shorten overall survival.
B-2 Cause-specific morbidity (or in combination with B-1) *a
Comment: similar as above (B-1)
C. Carefully assessed quality of life *b.
D. Indirect surrogates
1) Disease-free survival
2) Progression-free survival
3) Tumour response rate4) Scales and other measures *a
Source: Based on a hierarchy from the US National Cancer Institute website (http://www.cancer.gov/cancertopics/pdq/levels-evidence-adult-treatment/)*a: Added by the manual’s editors, to make it more applicable to otherdiseases and interventions.
*b: If “carefully assessed quality of life” is combined with overall survival,
the combined endpoint could be classified as A-2.(simplified from ref [1])determined for most of the products in the toxicity tests.
4) Death, arterial mineralization (calcification) [10]and
pheochromocytoma increased dose-dependently (figure 1,
figure 2a and figure 2b).
5) Although a patient died due to acute chronic pyelonephritis
with increased urine volume related to a SGLT-2 inhibitor, theagent was considered safe according to the manufacturer’s
claim, namely “these are the consequence of pharmacologicalaction of SGLT-2 inhibitor” concluding "it is not a toxic sign of
the SGLT-2 inhibitor."
As a result, the regulator concluded the SGLT-2 inhibitor"is safe for use in practice."
Abstract of Med Check TIP 2015; 15 (#58); pp. 35-36.
By mid-February 2015, the number of deaths related to theuse of SGLT-2 inhibitors increased to 17 patients in total. It
was revealed in the authorized documents that all problems
warned againts by diabetologists just after marketing were
well known during the clinical trials and were presented
during the discussion on approval of SGLT-2 inhibitors bydrug regulators. In other words, the following problems werealready known in all SGLT-2 inhibitors before their marketing
commenced [2-6]: (1) severe hypoglycemia, (2) urinary
tract and genital infections, (3) pollakiuria and polyuria, (4)dehydration, disruption of body electrolyte balance, weight
loss, (5) incease of ketone body , (6) adverse effect on bone

MED CHECK - TIP APRIL 2015 / Vol.1 No.1 ・ Page New Products
Figure1 ： Mortality in mice carcinogenicity study(ipragliflozin, male)

N=60 for each dose group. Chi square for linear trend was significant(P<0.0001) at 52w with the assumption of 16 deaths (similar to that at 48
w in the highest dose groups. The results at 78W and 97W, for trend werep=0.002 and p<0.0001 without including the highest group. Mortality inthe lowest group (50 mg/kg) was significantly higher than control groupboth at 78w (OR=3.35; 95％ CI: 1.12 to 10.0, p=0.0244) and at 97w (OR=2.33, 95%CI; 1.10 to 4.93, p=0.0253). Hence, safe dose in which deaths do
not occur was not determined in this toxicity study.

Figure 2 Dose-related findings in the rat carcinogenicity
study(a) tofogliflozin

were also observed for some products. Potential harm to thecentral nervous system is predicated on the fact that nerve
cells have SGLT-2 receptors with signs and symptoms ofneuropsychiatric toxicities being observed in animal toxicity
tests. Toxicities may be problematic especially in the elderly.
Although carcinogenicity was not aparent in the
animal experiments excepting an increase in adrenal
pheochromocytoma, clinical trials of dapagliflozin showedthat cancers in all sites were observed more frequently withstatistical significance in the dapagliflozin group (25/5936)
compared to the control group (4/3403): odds ratio 3.59 (95%
CI: 1.25 to 10.34, p=0.011). Increases in breast cancer (12 vs2) and bladder cancer (5 vs 0) were especially noted.
In the trials of other SGLT-2 inhibitors such as ipragliflozin,luseogliflozin and canagliflozin, cancers were reported more
frequently in the active arms than in the control groups: odds
ratio was 1.1 for canagliflozin and 4.3 for ipragliflozin (notstatistically significant).
Bladder cancer may increase in predisposed patients
through stimulation from persistent inflammation in the
bladder with long-term bladder expansion due to increased
urinary volume.
In conclusion, all problems of SGLT-2 inhibitors revealed
just after marketing were already known before approval.
Even if the fasting glucose level and HbA1c are improved,
neither improvement in metabolism nor in prolongation oflife is expected in diabetic patients by SGLT-2 inhibitors.
SGLT-2 inhibitors should be banned. We strongly
recommend physicians not to prescribe them.
References(b) canagliflozin

concentration, (7) cardiovascular risk, and (8) malignant
tumours.
Renal, hepatic and gastrointestinal adverse reactions

Page  ・ MED CHECK - TIP APRIL 2015 / Vol.1 No.1

1) International Society of Drug Bulletins and World Health Organization. Starting or
Strengthening a Drug Bulletin: A Practical Manual 2005. Chapter 8. Reviewing a new
drug: is it a therapeutic advance? Available at:
http://www.isdbweb.org/documents/uploads/manual_full_text.pdf
2) Approval dossier: ipragliflozin (in Japanese)a)Summary basis of approval
http://www.info.pmda.go.jp/shinyaku/P201300172/index.htmlb)Examination result report by PMDA
www.info.pmda.go.jp/shinyaku/P201300172/800126000_22600AMX00009000_A100_1.pdf
3) Approval dossier: tofogliflozin (in Japanese)a)SBA:www.info.pmda.go.jp/shinyaku/P201400036/index.htmlb)Examination result report by PMDA
www.info.pmda.go.jp/shinyaku/P201400036/780069000_22600AMX00549_A100_1.pdf
4) Approval dossier: dapagliflozin (in Japanese)a)SBA: http://www.info.pmda.go.jp/shinyaku/P201400016/index.htmlb)Examination result report by PMDA
www.info.pmda.go.jp/shinyaku/P201400016/670605000_22600AMX00528000_A100_1.pdf
5) Approval dossier: Luseogliflozin (in Japanese)a)SBA:http://www.info.pmda.go.jp/shinyaku/P201400033/index.htmlb)Examination result report by PMDA
www.info.pmda.go.jp/shinyaku/P201400033/400059000_22600AMX00540_A100_1.pdf
6) Approval dossier: canagliflozin (in Japanese)a)SBA:http://www.info.pmda.go.jp/shinyaku/P201400070/index.htmlb)Examination result report by PMDA
www.info.pmda.go.jp/shinyaku/P201400070/22600AMX00744000_A100_1.pdf
7) Recommendation by “The Committee on proper use of SGLT-2 inhibitors” (in Japanese)
available at:
http://www.jds.or.jp/modules/important/index.php?page=article&storyid=48
8) Vrhovac I, Balen Eror D, Klessen D et al. Localizations of Na+-D-glucose cotransporters
SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung,and heart. Pflugers Arch. 2014 Oct 11, [Epub ahead of print]9) Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern
Med. 2007; 261(1):32-43.
10) Kumar V et al eds “Robbins Basic Pathology” 7th ed Philadelphia, Saunders 2003.
11) Levison ME and Pitsakis PG. Effect of insulin treatment on the susceptibility of thediabetic rat to Escherichia coli-induced pyelonephritis. J Infect Dis. 1984; 150: 554-560.

New Products

Methadone :Limited use:
Useful only in opioid rotation with special precautions
Translated as synopsis from Med Check TIP 2015; 15 (Mar; #58); 27-30.

Synopsis:Methadone hydrochloride (“methadone”, brand name:Methapain)[1] was first synthesized in Germany in 1937.
It was approved in the United States in 1947 as an opioid.
Vincent Dole et al. reported in 1964 that it was useful asan alternative therapy for patients with drug addiction [2].
It subsequently came into worldwide for the treatment ofpatients with drug addictions [2].
After methadone was approved as a strong analgesic in
the United States, it subsequently was approved in many
countries since around 1990. In Japan, methadone did notstart to be marketed until March 2013, after it was finallyapproved in September 2012
Methadone has a high affinity to an opioid μ receptor
similar to common opioids including morphine [1]. In
addition, it acts as an antagonist to N-methyl-D-aspartate(NMDA) receptor [1]. Because of the latter effect, it is used as
one of the most important medicines in the “opioid rotation
therapy” for the patients who do not respond to and/or havebecome tolerant to common opioids such as morphine or
oxycodone [4]. It will be a boon to patients who suffer fromrefractory pain if used appropriately. However, it could easily
induce serious harm including respiratory arrest and/or lethal
arrhythmia with an overdose if not used appropriately. It is
well known that there have been many fatalities [5,6].
Due to the characteristic pharmacokinetics of methadone,
dose adjustment may be difficult. In order to prevent serious
harm induced by methadone, it is essential for prescribers
to know pharmacokinetics and interactions of methadone
well, and to carefully consider the clinical conditions of thepatients.
For switching from morphine or oxycodone to methadone,
3DS method (3 days switch method) is superior [16].
Supplement to the synopsis:
Serious clinical condition resulting in death: Respiratory
suppression and lethal arrhythmia
Pathophysiologic conditions resulting in death frommethadone overdose include respiratory suppression
and lethal arrhythmia. In order to prevent these deaths,
prescribers should be aware of the risk factors which
exacerbate these conditions so that they can be avoided.
Risk factors that could exacerbate respiratory suppression
are: old age, liver dysfunction, sleep apnea syndrome,concomitant substances (including alcohol use, benzodiazepines and antidepressants), excessive-dose and/or rapidly
increased dose of methadone.
The risk factor that could exacerbate lethal arrhythmia( Torsades de Pointes) are: female gender, electrolyte

abnormality (e.g. low potassium and magnesium levels),
history and complication of heart diseases (especially heart
failure), bradycardia, diabetes, QT prolongation, concomitant
use of drugs that prolong QT time (e.g. antiarrhythmic agents,
neuroleptic, tricyclic antidepressants, cilostazol, azithromycin,
moxifloxacin and oseltamivir).
Characteristic Pharmacokinetics of Methadone
Methadone is metabolized by CYP3A4 and CYP2B6 and isable to self-induce these enzymes. The elimination half-life isreduced after longer periods of use. Conversely, during theearly phase of commencement, the elimination half-life ofmethadone is long. Hence, the risk of accumulation is higher
in the initial phase, extra caution is necessary especiallyduring the first 4 to 6 days after initial use.
Interaction is associated with the followings: methadone
is metabolized by CYP3A4 and CYP2B6, and it is one of thesubstrates of p-glycoprotein.
Azole-based antifungal agents and macrolide derived
antibiotics raise the blood level of methadone by CYP3A4
antagonists. The paroxetine raises blood level of themethadone by CYP2D6 antagonists. Rifampicin, phenytoin
and carbamazepine induce metabolising enzymes, promote
the metabolism of methadone, and reduce blood level.
Because p-glycoprotein inhibits absorption via the gastrointestinal tract and is an efflux transporter at the blood-brain
barrier to prevent increasing methadone levels in plasma andin the brain, p-glycoprotein antagonists such as cyclosporine
or clarithromycin may increase methadone levels.
The clinical condition of high risk patients:
Renal failure: Dose reduction and prolongation of the intervalof dosing are recommended in patients suffering from renal
failure. Methadone in the system is largely unaffected byhaemodialysis or peritoneal dialysis.
Liver damage: Because the prolongation of the elimination
half-life is reported in patients with severe liver damage,
methadone use should be avoided in them. The use of
methadone is restricted even in patients with mild tomoderate liver disease.
Elderly people: Because renal, hepatic, cardio-pulmonary,and other physiological conditions including neurological
functions, are all reduced, careful management is essential,
especially to prevent respiratory failure or fatal arrhythmias.
Conversion methods in opioid rotation:
Two methods are available for rotation from other opioids
to methadone. One is the SAG method (Stop And Go method:
discontinue previous opioids, and start methadone promptly).

MED CHECK - TIP APRIL 2015 / Vol.1 No.1 ・ Page New Products
The other is the 3DS method (3 Day Switch method: tapering
previous opioids for three days and gradually increasing
methadone).
Moksnes et al.[16] compared these two methods for the
first time in a prospective randomized controlled trial. Thirtyfive participants with cancer who had been taking relatively
high-doses of morphine or oxycodone were divided into
two groups with each placed on one of the two switching
methods. The SAG method was used in 16 patients (average
dose was 900 mg/day of equivalent oral morphine dose),and the 3DS method was used in 19 patients (average dose
was 1,330 mg/day). More patients withdrew due to serious
adverse events in the SAG method group: six serious adverse
events including two deaths due to myocardial infarction andpulmonary embolism occurred in the SAG group. On the other
hand, only one adverse event occurrence was reported in the
3DS group. The odds ratio was 10.8 (p=0.0318). In addition,in the SAG group, pain management was poorer than thatin 3DS group [16]. It should be concluded that the 3DS
method is superior to SAG method both in terms of treatment
adherence and pain management.
No "Plain Language Summary" is available for this drug, because
this is a very specialized drug highly restrictive use in patients.

Page  ・ MED CHECK - TIP APRIL 2015 / Vol.1 No.1

References
1 - Approval dossier of Methadone (all in Japanese)1a) Summary basis of approval http://www.info.pmda.go.jp/shinyaku/
P201200139/index.html
1b)Examination result report (September 2012）、 1c) labeling of methadone.
2 - Shah S.and Diwan S. Methadone: Does stigma play a role as a barrier totreatment of chronic pain? Pain Phys 2010; 13: 289-293.
3 - Inturrisi C.E. Pharmacology of methadone and its isomers. Miner anest
2005; 71: 435-7.
4 - Fine PG, Portenoy RK, Ad Hoc Expert Panel on Evidence Review and
Guidelines for Opioid Rotation. J Pain SymptManage 2009;38:418–25.
5 - Milroy CM and Forrest AR. Methadone deaths: a toxicological analysis. J
clin path 2000; 53: 277-81.
6 - Webster LR, Cochella S, Dasgupta N, et al. An analysis of the root causes
for opioid-related overdose deaths in the United States. Pain Med 2011; 12:
S26-35.
7 - Faggiano F, Vigna-Taglianti F, Versino E, et al. “Methadone maintenanceat different dosages for opioid dependence” (Cochrane review) (last update2003). In: “Cochrane Database of Systematic Reviews” .
8 - Webster LR, Fine PG. Review and critique of opioid rotation practices andassociated risks of toxicity. Pain Med. 2012 Apr;13(4):562-70
9 - Pubchem. National Center for Biotechnology Information. Compound
Summary for CID 14184; Methadone Hydrochloride. http://pubchem.ncbi.
nlm.nih.gov/compound/14184#section=Solubility
10 - Ebert B, Andersen S, Krogsgaard-Larsen P. Ketobemidone, methadone
and pethidine are non-competitive NMDA antagonists in the rat cortex andspinal cord. Neuroscience Letters 1995; 187(3):165-8.
11 - Brunton LL, Chabner BA, Knollmann BC. Goodman & Gilman’s The
Pharmacological Basis of Therapeutics 12th Ed. New York McGraw-Hill,
2011: 506.
12 - Mokubu H, Tomiyasu S, Tanda S et al. Pharmacokinetics of methadone.
Palliative Care Research 2014; 9(4): 401-11.(in Japanese)
13 - Chugh SS, Socoteanu C, Reinier K,et al. A Community-Based Evaluationof Sudden Death Associated with Therapeutic Levels of Methadone. The
American journal of medicine 2008; 121(1):66-71.
14 - FDA Public Health Advisory. Methadone Use for Pain Control May
Result in Death and Life-Threatening Changes in Breathing and Heart Beat.
http://www.nascsa.org/News/FDAmethadonePublicHealthAdvisory12.06.pdf
15 - Leppert W. The role of methadone in cancer pain treatment-a review. Int J
Clin Pract 2009; 63(7): 1095-109.
16 - Moksnes K, Dale O, Rosland JH, et al. How to switch from morphine or
oxycodone to methadone in cancer patients? A randomized clinical phase II
trial. European Journal of Cancer 2011; 47: 2463-70.
17 - Ripamonti C, Groff L, Brunelli C, et al. Switching from morphine to oral
methadone in treating cancer pain J Clin Oncol 1998; 16(10): 3216-21.
18 - Lawlor PG, Turner KS, Hanson J, et al. Dose ratio between morphine andmethadone in patients with cancer pain. Cancer 1998; 82: 1167-83.
19 - Walker PW, Palla S, Pei BL, et al. Switching form methadone to adifferent opioid: J Pall Med 2008; 11(8): 1103-8.

Review
H. pylori eradication may shorten life span
Gastric cancer risk decreases, but, incidence of C. difficile infections and pneumonia increases

Abstract:
Proton pump inhibitor (PPI) usage increases the risk of Clostridium difficile (C. difficile) infections. Underlying factors for thisphenomenon include the high prevalence of asymptomatic C. difficile carriage, and vacuolar proton pump (V-ATPase) inhibition in
every eukaryotic cell by PPI resulting in cell function impairment. Efficacy of H. pylori eradication in asymptomatic carriers needs
to be evaluated by weighing potential benefits against any detrimental effects including increased infection risk and taking
overall long-term survival rates into account. Meta-analysis of long-term randomized controlled trials (RCTs) showed decreasing
gastric cancer incidence and non-significant increases in all-cause mortality in the H. pylori eradicated group vs. the noneradicated. Hence, H. pylori should not be eradicated in otherwise healthy carriers.

Introduction
The need of metronidazole use has been increasing due
to recent rises in C. difficile infections [1a]. However, thecontinuous use of metronidazole induces neuropathy (bothperipheral and central) dose-dependently [1b]. Increases in C.
difficile infections are attributable to the use of proton pumpinhibitors (PPIs) [2].
We reviewed the mechanisms behind increased C. difficile
infections in the context of PPI usage and its long-term
outcomes including overall survival rates.
The following points will be discussed:(1) Natural history of C. dif
ficile infections(2) C. difficile infection risk factors: including PPI, antibiotics
and anticancer agents(3) Effects on overall survival rates in long-term RCTs
(4) PPI inhibits proton pump activity in gastric parietal cells
and V-ATPase in systemic cells(5) Mechanism behind increased mortality risk

Figure 1. C. difficile carriage in infants: trends by age(Comparison: Japan and France)(1) Prevalence of C. difficile carriage is highPrevalence of asymptomatic C. dif
ficile carriage in neonates
is lower than that in mothers. However, 100 % of affected
infants were infected during the first 12 months after birthand prevalence fell subsequently [3] (figure 1). In France,a year-long monthly follow-up study involving 10 healthy
infants to determine the incidence of intestinal C. difficile
colonization was conducted. [4]. All subjects became infectedwith C. dif
ficile during the first 6 months after birth [4]. A crosssectional study revealed that the prevalence of asymptomatic
carriage fell to 6% in 2 year old infants, the same level as inadults [4] (figure 1). The prevalence of asymptomatic carriage
of C. difficile in Japanese infants is significantly higher than in
French infants: odds ratio (OR) = 7.1 (95% CI: 2.5, 19.9, p=0.0002).
The prevalence of C. difficile colonization among Japanese
adults is reported as 7.6%, which is comparable to that inother countries [5]. It is reported [9] that the prevalence of
C. difficile colonization among patients with recent inpatient
healthcare exposure is at least double (7%–17%) that ofpatients without inpatient healthcare exposure (3% –7% ).

(2) PPI increases CDAD incidence two- to seven fold
Use of gastric acid antagonist drugs such as PPI, Histamine-2
antagonists (H2-bl) and sucralfate was reported as a C. dif
ficileassociated diarrhea (CDAD) risk factor in a 1994 casecontrol study [10]. However in this study, no risks associatedwith the breakdown of gastric acid antagonists were reported.
In 2003 (a case-control study) [11] and 2004 (a case-control
and a cohort study) [12], PPI was reported as an independentrisk factor for CDAD. Since 2008, some similar reports andseveral meta-analyses followed [13-16].
Among these, the meta-analysis by Deshpande et al [14] ismost reliable because case-control studies and cohort studies
were meta-analysed separately. Pooled odds ratio (POR) of
PPI for CDAD was 1.78 (95% CI: 1.41, 2.25, p<0.0001) using
cohort studies and 2.22 (1.82, 2.70, p<0.0001) for casecontrol studies.
In a study by Dial et al [12], analysing the risk of CDAD
among long-term PPI users (6 months or more), the hazard
ratio (HR) was 6.9 (95% CI: 2.3 to 20.8, p=0.0001), compared
to 3.1 (95% CI: 1.7 to 5.6, p=0.0001) for any duration of PPI

Note: French study includes a 36.2-month old child in 2-year
old group. Pooled odds ratio (POR) using data of 0-year olds,
1-year olds, and 2 year olds is 7.1 (95% CI: 2.5, 19.9, p=0.0002).

MED CHECK - TIP APRIL 2015 / Vol.1 No.1 ・ Page Review
use. (Table 1) Recurrent CDAD risk associated with PPI use
calculated using the data of Dial et al. [12] was very high: OR= 16.8 (Table 1).
PPI, antibiotics and anticancer drugs constitute independentrisk factors [11]. When antibiotics and PPI were combined,
the OR was 5.4. When all three factors were combined, OR
was 43.2 [11]. (Table 1)H2-blocker exposure was also revealed as a risk factor for
CDAD by meta-analysis [17]: POR was 1.44 (1.22-1.70).

Table 1: C. difficile infection risk factors

pathogenic agents, including envelope viruses and bacterial
toxins. V-ATPases are present in the plasma membrane ofrenal cells, osteoclasts, macrophages, epididymal cells andcertain tumour cells where they are important for urinary
acidification, bone resorption, pH homeostasis, sperm
maturation and tumour cell invasion, respectively. PPI
inhibits not only the proton pump of gastric parietal cells (H+/
K+ATPase) but also V-ATPases [7].
As a result, PPI inhibits immune response and inflammation
during infections or in situations where tissue repair isnecessary. It could affect bone metabolism as well as
neurological and renal functions, among others. [7, 8].

CCAD: C. difficile associated diarrhea, CI: confidence interval(5) Mechanisms behind increased mortality risk
Increases in all-cause mortality after H. pylori eradication
using PPI may be related to the mechanisms that inhibit
vacuolar proton pumps which is present in every cell and has
an important role in maintaining the functions of each cell.
Based on above-mentioned examination results, we proposea hypothesis on the natural history of C. dif
ficile infections andthe effects of medical intervention as shown in figure 2.

Table 2: Gastric cancer incidence and mortality, cancer mortality(all sites) and all-cause mortality(source: RCT with longest follow up duration [19])(3) Possibility of higher PPI-associated all-cause mortality risk
A meta-analysis of RCTs reporting among the long-term (4to 15 years) outcomes after H. pylori eradication was reported[18]. In this study, gastric cancer incidence decreased withpooled relative risk (RR) at 0.66 (0.46, 0.95). However, theeradication group showed a non-significant increase in allcause mortality compared with the placebo (untreated) group:pooled OR = 1.10 (0.89, 1.37). To date, long-term outcomes
after H. pylori eradication in asymptomatic carriers have beenreported primarily in Asian subjects.
The results from an RCT with a long-term follow-up (15years) [19] showed non-significant increases of adjusted HR
for all-cause mortality rates in the eradicated group: 1.14
(0.90, 1.46, p= 0.28). In populations with low gastric cancer
mortality, all-cause mortality risk may be higher.

(4) The proton pump is essential to maintain the normal
functions of many cells
The vacuolar (H+)-ATPases (V-ATPases or “vacuolar proton
pumps”) are ATP-dependent proton pumps responsible
for both acidification of intracellular compartments and,for certain cell types, proton transport across the plasma
membrane [8]. Intracellular V-ATPases function in both
endocytic and intracellular membrane traffic, the processing
and degradation of macromolecules in secretory and digestive
compartments, the coupled transport of small molecules
such as neurotransmitters and ATP as well as the entry ofPage  ・ MED CHECK - TIP APRIL 2015 / Vol.1 No.1

Figure 2
A hypothesis on the natural history of CD infections
and the effects of medical intervention

CD: C. difficile , PPI: Proton pump inhibitor, H2-bl: H2 blocker
In practice
Asymptomatic H. pylori carriers should not be eradicated. Westrongly recommend against repeated eradication regimens.
It is necessary for prescribers to only use PPI for short-term
treatment of peptic ulcers (6 weeks for duodenal ulcer and8 weeks for gastric ulcer) as recommended in the labelingof PPIs. Long-term outcomes of combination regimens
combining PPI and non-steroidal anti-inflammatory drugs(NSAIDs) for rheumatoid arthritis or low-dose aspirin forprevention of thrombotic diseases have never been assessed
for all-cause mortality, the strongest endpoint of treatment[see p3 Table 1] [a].
We recommend against long term use of PPI for reflux
oesophagitis or non-erosive gastroesophageal reflux.
[a]: One patient in the lansoprazole group (n=62) succumbed to pneumonia
after a stroke in a randomized controlled trial with 123 participants in bothgroups and followed for one year [20].

References
1 - a) Check Med TIP team. Metronidazole. Check Med TIP: 2015 Jan:15(57) ： 8-11.
b) Check Med TIP team. Neurotoxicity of metronidazole. Check Med TIP:
2015 Mar.: 15(58):40-41.
2 - Prescrire team, Proton pump inhibitors: Clostridium difficile infection.
Prescrire International 2013: 22 (142): 239-240.
3 - Matsuki S, Ozaki E, Shozu M et al. Colonization by Clostridium difficileof neonates in a hospital, and infants and children in three day-carefacilities of Kanazawa, Japan. Int Microbiol. 2005;8(1):43-8.
4 - Rousseau C, Poilane I, De Pontual L et al. Clostridium difficile carriage
in healthy infants in the community:.Clin Infect Dis. 2012; 55(9):1209-15
5 - Kato H, Kita H, Karasawa T et al. Colonisation and transmissionof Clostridium difficile in healthy individuals. J Med Microbiol.
2001;50(8):720-7.
6 - Galdys AL, Curry SR, Harrison LH. Asymptomatic Clostridium difficile
colonization as a reservoir for Clostridium difficile infection. Expert Rev
Anti Infect Ther. 2014;12(8):967-80
7 - Kedika RR, Souza RF, Spechler SJ. Potential anti-inflammatory effects
of proton pump inhibitors: a review. Dig Dis Sci. 2009;54(11):2312-7.
8 - a)Cipriano DJ, Wang Y, Bond S et al. Structure and regulation of thevacuolar ATPases. Biochim Biophys Acta. 2008;1777(7-8):599-604b)Jefferies KC, Cipriano DJ, Forgac M. Function, structure and regulationof the vacuolar (H+)-ATPases. Arch Biochem Biophys. 2008 Aug
1;476(1):33-42
9 - Alasmari F, Seiler SM, Hink T et al. Prevalence and risk factors
for asymptomatic Clostridium difficile carriage. Clin Infect Dis.
2014;59(2):216-22
10 - Nath SK, Salama S, Persaud D et al. Drug risk factors associated witha sustained outbreak of Clostridium difficile diarrhea in a teaching hospital.

Can J Infect Dis. 1994;5(6):270-5
11 - Cunningham R, Dale B, Undy B, Gaunt N. Proton pump inhibitors as arisk factor for Clostridium difficile diarrhoea. J Hosp Infect. 2003;54(3):243-5
12 - Dial S, Alrasadi K, Manoukian C et al. Risk of Clostridium difficile
diarrhea among hospital inpatients prescribed proton pump inhibitors: cohortand case-control studies. CMAJ. 2004;171(1):33-8.
13 - Garey KW, Sethi S, Yadav Y, DuPont HL. Meta-analysis to assess
risk factors for recurrent Clostridium difficile infection. J Hosp Infect.
2008;70(4):298-304.
14 - Deshpande A, Pant C, Pasupuleti V et al. Association between proton
pump inhibitor therapy andClostridium difficile infection in a meta-analysis.
Clin Gastroenterol Hepatol. 2012;10(3):225-33.
15 - Kwok CS, Arthur AK, Anibueze CI et al Risk of Clostridium difficile
infection with acid suppressing drugs and antibiotics: meta-analysis. Am J
Gastroenterol. 2012;107(7):1011-9.
16 - Tleyjeh IM, Bin Abdulhak AA, Riaz M et al. Association between proton
pump inhibitor therapy and lostridium difficile infection: a contemporary
systematic review and meta-analysis. PLoS One. 2012;7(12):e50836
17 - Tleyjeh IM, Abdulhak AB, Riaz M et al. The association between
histamine 2 receptor antagonist use and Clostridium difficile infection: asystematic review and meta-analysis. PLoS One. 2013;8(3):e56498.
18 - Ford AC, Forman D, Hunt RH et al. Helicobacter pylori eradication
therapy to prevent gastric cancer in healthy asymptomatic infectedindividuals: systematic review and meta-analysis.BMJ. 2014;348:g3174.
19 - Ma JL, Zhang L, Brown LM et al. Fifteen-year effects of Helicobacter
pylori, garlic, and vitamin treatments on gastric cancer incidence andmortality. J Natl Cancer Inst. 2012;104(6):488-92
20 - Lai KC, Lam SK, Chu KM et al. Lansoprazole for the prevention ofrecurrences of ulcer complications from long-term low-dose aspirin use.
NEJM.2002;346(26): 2033-

Harm of HPV vaccine:
Latest information and examination of epidemiological studies

Abstract: According to the latest pharmacovigilance data, the incidence of serious adverse reactions to HPV vaccine is 3.2%
per year (3,200 cases per 100,000 person-years). This is similar to the incidence rate of serious adverse events within 1.2
years after the first vaccination (annual rate of 2.8%) reported in randomized controlled trials (RCT) for Cervarix. In Cervarix
RCTs, the excess incidence of serious reactions, autoimmune diseases and death after 3.4 years compared with reactions
from 1.2 to 3.4 years was respectively calculated to be 4,000 patients, 630 patients and over 100 deaths per 100,000
person-years. These might also occur in Japan. The epidemiological surveys from Europe and North America that Japan’s
Ministry of Health, Labour and Welfare (MHLW) used as evidence for safety of the vaccine have flawed methodologies. One
study confused prevalence with incidence, and the other two have serious risk of bias attributable to the "healthy vaccinee
effect". While there is no evidence yet confirming that HPV vaccination decreases the incidence of and mortality from cervicalcancer, assuming that the vaccine could halve cervical cancer mortality, the expected maximum benefit would be 2.0 deaths
per 100,000 person-years. Hence, the harm experienced to date is overwhelmingly greater than the benefit expected.

Introduction
The NPO Japan Institute of Pharmacovigilance (NPOJIP)
has repeatedly discussed the harmful effects of HPV vaccine
in the Informed Prescriber (TIP) [1-4], “Med Check” [5-9] andthe “On-line Med Check” [10]. In 2014, reports of diseases
with intense symptoms appeared one after another. They
were so severe that experts on neurologic intractable diseases,

childhood collagen diseases and fibromyalgia unanimously
stated that they had never seen such serious diseases before[11]. As of September 2014, more than two hundred suchserious cases had been reported [12].
Although the MHLW withdrew its active recommendation
after 14th June 2013, it denied the causality of HPV
vaccination in the subsequent onset of severe symptoms, and

MED CHECK - TIP APRIL 2015 / Vol.1 No.1 ・ Page Review
has not retracted the “Psychosomatic Reaction Theory [13].”Moreover on the association with autoimmune diseases, the
MHLW has not overturned its conclusion that the vaccine
is safe [13] by referring to several epidemiological studies[14-17].
This review primarily examines the problems foundin the epidemiological studies that the MHLW uses as abasis for determining the safety of the vaccine. In addition,
it introduces the result of the latest analysis of serious
adverse reactions, and compares the harms with the possible
maximum benefit of HPV vaccination. We also respond tosome criticisms [18] on the method of analysis we employed
previously, and discuss that the MHLW and HPV vaccination
advocates have little evidence to support their claim.
No need to compare incidence of serious reactions with lifelong
mortality: One year for mortality is enoughWe first published an article assessing the potential
benefits and harms of HPV vaccines in April 2013 [1] (Seea brief description on p 13). Some criticisms to our article
appeared aubsequently. Of these, Kinugasa[18] criticised
our methods of analysis. He point out that we used annual
mortality instead of lifetime mortality that is higher by several
orders of ten than the former making it fundamentally flawed.
After the active recommendation of the vaccine waswithdrawn, serious reactions became apparent even longafter HPV vaccine administration. The article concerned[1] was written before the active recommendation waswithdrawn, and at that time, approximately 800 cases ofserious reactions had been reported out of 2,600,000 persons
vaccinated with HPV vaccine (30 cases per 100,000 persons).
Serious reactions after inoculation disclosed by the MHLW
include reports both from pharmaceutical companies anddirectly from doctors. The MHLW limited the reporting of
events to those that occurred within 30 days of inoculation.
In fact, cases involving serious reactions occurring later than
one month were extremely rare (0.5% of the cases reported).
Therefore, data on cases with adverse reactions should havebeen collected even beyond one year after inoculation.
On the other hand, there is no evidence yet to provethat HPV vaccines reduce the incidence of cervical cancer
fatalities. Even if we assume that the vaccine can cut theincidence of cervical cancer in half, the expected decrease
will only be 2.0 per 100,000 person-years. In order tobalance the benefits and the serious reactions within one
month after inoculation, the potential benefit must be 0.2 per
100,000 person-years (one-twelfth of the annual maximum
preventable mortality). It is not necessary to compare thefrequency of serious adverse reactions to HPV vaccine withlifelong cumulative cervical cancer mortality.
Annual incidence of serious reaction is 3.2% in Japan:
Meanwhile, since the active recommendation was
retracted in June 2013, it has become well known thatthe vaccine might induce serious harms even long after
inoculation. Out of 217 persons who were vaccinated with
Cervarix between 1st August and 30th September 2013
(after the harms became well known), four cases of serious
reactions were reported by 31st March 2014 [13b]. Since
the four cases of serious reactions were reported during an
average seven-month follow-up period, the annual incidence

Page 10 ・ MED CHECK - TIP APRIL 2015 / Vol.1 No.1

amounts to 3.2% (95% CI: 0.9-7.9), which means 3,200 per
100,000 person-years. Assuming that the maximum expectedannual preventive effect is 2.0%, the incidence of serious
reactions to the vaccine is more than 1,500 times higher.
This finding (3.2% per year) is almost equivalent to theannual incidence of serious adverse events within 1.2 years(2.8%; 95%CI: 2.6-3.1) in Cervarix RCTs (figure on p11)
[supplementary references]. The excess incidence or excess
mortality of serious adverse events, autoimmune diseases,
and death after 3.4 years over those from 1.2 to 3.4 years
in Cervarix RCTs are about 4,000, 630 and more than 100
deaths per 100,000 person-years respectively. Considering
these findings, serious reactions might occur after 3.4 years
at similar incidence rates also in Japan.
Four years have passed since the first marketing of
Cervarix in November 2010. After the active recommendation
was canceled and serious reactions to HPV vaccine become
well known, autoimmune disease, dysfunction in brain
and/or serious neuropathy occurring long after inoculation
have begun to be reported. As it is very likely that serious
adverse reactions would occur in the future, those who were
vaccinated should be under close monitoring.
Epidemiological studies on HPV vaccine and autoimmune
diseases:
Japan's MHLW states "No evidence for causality between
the HPV vaccine and known autoimmune diseases such as
rheumatoid arthritis and SLE was evident in cases involving
extensive pain or motor disturbance.”
This is based on the following five epidemiological studies:a systematic review of RCTs [14], Siegrest’s paper [15], Gee’s paper [16], Arnheim-Dahlstrom’s paper [17] and Institute ofMedicine of the National Academies (IMNA) report. Kinugasa[18] based his argument only on the Arnheim-Dahlstrom
article. This review examines these published articles except
for the IMNA report which remains unpublished..
a) Safety cannot be proven by RCTs of two vaccines thatused problematic adjuvant (preparation) in both the active andcontrol groups:
The MHLW remarked on the result of the systematic review
and the meta-analysis [14] that there was no difference inrisk of adverse events between the vaccinated and control
groups. However, in all RCTs examined in the systematic
review, potentially harmful adjuvants or adjuvanted products
were used as the control: alum adjuvant for Gardasil andalum adjuvanted hepatitis-A vaccine for Cervarix. Therefore,
even though there was no difference in harm between thetwo groups, it may be too early to conclude that the vaccine
is safe. Because the incidence of adverse events fluctuatessignificantly over time [4,6], it may be reasonable to consider
that the adverse effects of HPV vaccine are in part due toadjuvants.
As the harms of adjuvants are also discussed in otherpapers [2,8,9], this review does not do so in detail. The
problems of epidemiological studies that claim the safety ofthe vaccine are described in the following sections.
b) A study that confused prevalence with incidence:
Siegrist et al. [15] calculated the “frequency” by using
the number of health insured females aged 9-18 and 19-30

years old as a denominator and the number of persons
autoimmune diseases is observed among vaccinated people, it
who consulted a doctor (outpatient, emergency andwill simply be offset by the diseases in sickly non-vaccinatedhospitalization) at least once in 2005 as a numerator. The
people. This is the “healthy vaccinee effect.”
MHLW estimated the expected number of patients withIn the Gee article, selection criteria for the control group
autoimmune diseases in 3,300,000 vaccinated persons. For
are not clearly stated. This alone is enough to make theexample, as multiple sclerosis occurred one per 100,000
study unreliable. Additionally, it is likely that outpatients
person-years in the Siegrist study, the MHLW calculated
who consulted for any reasons other than vaccination werethat 30 cases are expected to occur in 3,300,000 persons
selected for the control group. This means that the control
inoculated with HPV vaccine in Japan.
group included many patients with infections, increasing the
However, the “frequency” Siegrest et al. showed is notincidence of autoimmune diseases at the start of follow-up.
the “incidence” (or newly occurred disease among certain
Therefore, they are unsuited as a control group of healthy
population within a certain period of time). Their frequency isvaccinated people.
the “prevalence” (or a proportion of persons having a disease
Arnheim-Dahlstrom et al. [9] conducted a follow-up study
among certain population at a certain point in time). Sinceof approximately one million girls aged 10-17 years old
autoimmune diseases do not easily remit, prevalence is 10-30
between 2006 and 2010, utilizing a database in Swedentimes higher than incidence in general. For instance, in theand Denmark. Some 300,000 girls received at least one
case of multiple sclerosis, the ratio of prevalence to incidence
dose of Gardasil (average 2.35 doses), and were observedin various countries is about twenty on average [19]. This
for 180 days after inoculation. After adjusting for theirshows that the “frequency” Siegrist et al. reported cannot
age, educational background of parents, and the year of
be the “incidence” of autoimmune diseases and cannot be
inoculation, incidences of fifty-three kinds of neurologicalcompared with autoimmune diseases that newly occur after
disorders, autoimmune diseases and venous thrombosis
inoculation of the vaccine.
were analyzed, and the risk ratio with the control was
According to Siegrist et al., 11 out of approximately
calculated. As a result, among twenty-nine diseases analyzed,
215,000 women aged 9-18 years old consulted a doctor fortwenty-three autoimmune diseases appeared in five or more
multiple sclerosis/optic neuritis once or more in the study
vaccinees. Of these, there was no significant difference foryear. As the prevalence is 5.1 per 100,000 person-years, the
20 diseases, but the incidence was significantly higher in theincidence is assumed to be approximately 0.25 per 100,000
Gardasil group for three diseases, namely Behcet’s disease
person-years. It is lower than the incidence of multiple(risk ratio 3.37), Raynaud's disease (risk ratio 1.67) and Typesclerosis for the women of the same age group in general
I diabetes mellitus (risk ratio 1.29).
population (1 to 5 per 100,000 person-years) [7]. For one
In the case of influenza vaccination, vaccinees were lessmonth, it can be converted to 0.021 per 100,000 personprone to influenza infection than non-vaccinated people.
months or 0.7 per 3,300,000 person-months.
After adjusting for the usual health conditions of children,
Incidence of multiple sclerosis among Japanese is lower
there is no difference in incidence of influenza at all between
than one-tenth that in the West [19-20]; thus, it is very
the vaccinated and the non-vaccinated [22]. This is anotherlow. Therefore, even a single case of onset might signify
example of the “healthy vaccinee effect”. It is also true for thehigh incidence. Two cases of optic neuritis, four ADEM, oneelderly.
multiple sclerosis, and one demyelinating central nerve
As mentioned above, the causal relation between HPVdisorder have already been reported after HPV vaccination
vaccine and autoimmune diseases cannot be denied based[13]. Optic neuritis often signal the onset of multiple sclerosis,
on epidemiological studies on the incidence of autoimmune
and at least one case of ADEM is reportedly uncured anddiseases in various countries in Europe and North America.
possibly developing into multiple sclerosis. Demyelinating
Adjuvant lacking tissue-injury cannot be an effective
central nerve disorder and multiple sclerosis are almost
adjuvant:synonymous. This means that the incidence is extremely
high with three serious cases that may possibly be multiple
Kinugasa [17] assumes that many epidemiological surveys
sclerosis. Moreover, in Gardasil RCTs, incidenceof multiple sclerosis was 14.7 per 100,000
Figure: Incidence of serious reactions (events) after Cervarix: Japan* vs RCT
person-years [4,7], which is approximately
sixty-times that in Siegrist’s study.
c) Healthy vaccinee effect is not considered
The MHLW argues “There is no significant
increase of risks,” referring to Gee’s article.
The fundamental flaw of Gee and ArnheimDahlstrom is that they do not correct
substantial confounding bias caused by the“healthy vaccinee effect” [21, 22]. People
usually prone to fever and infection tend to
avoid vaccination. Hence, non-vaccinatedpeople are sicklier than vaccinated people
and autoimmune diseases often follow
infection. Therefore, even if high incidence of*Spontaneous serious adverce reaction reports in JapanMED CHECK - TIP APRIL 2015 / Vol.1 No.1 ・ Page 11

Review
deny the causal relation between the harm and inoculation of
adjuvant, referring to two studies [23, 24].
The case control study of DeStefano et al. [23] investigated
the relation between demyelinating central nerve disordersuch as multiple sclerosis and adjuvanted vaccine, andconcluded that there was no significant difference in thevaccine users between cases with demyelinating diseases andthe control group. However, this study also did not consider
the healthy vaccinee effect (it was not mentioned in thediscussion). Jefferson et al. [24] conducted a meta-analysis ofeight RCTs or quasi-RCTs in a systematic review of the effectof vaccine with or without adjuvant. All trials were low in
quality: the longest follow-up period was six weeks (one trial),
and two trials followed up patients for only 24 hours after
inoculation. Sustained pain observed in people who received
adjuvanted vaccine was approximately two times more thanthat in control (odds ratio 2.05 [95%CI: 1.25-3.38]). Longterm harms have never been investigated.
Harm of adjuvants was discussed in detail in TIP [2] andMed Check [8, 9]. In brief, aluminum adjuvant acts as an
adjuvant when it first injures tissues especially injected
intramuscularly. White blood cells accumulate to repair
injured tissue, phagocyte aluminum and die releasing
DNA. Although unbound DNA is easily digested by DNase,
protein-bound DNA becomes stabilized and acts as a realadjuvant to enhance innate immunity. If DNA and/or MPL(monophosphoryl lipid A), a very strong adjuvant derived
from salmonella endotoxin (lipid A) in Cervarix is alsostabilized by binding with aluminum nano-particles, they
act as ligands of TLR-4 from which innate immune reactions
start.
Vaccination with Cervarix is predicted to provide long-term
persistence with high antibody titre for up to 20 years [25].
This is induced by HPV virus-like protein particles boundto aluminum nano-particles and MPL remaining in tissues
for a long time. Hence, it can well be predicted that not only
antibody production would persist but also other excessive
immune responses would persist via innate immunity
stimulated by long-term persisting virus-like particle-adjuvant
complex in various tissues including the central nervous
system.
Conclusion:
As the harms of HPV vaccine became well known, many
serious adverse reaction cases were reported long after
injection including unprecedented “severe reactions”, whichwere completely new even to specialists in neurology andcollagen disease of childhood. Because the risk of autoimmune
disease is estimated to be several hundred-times higher andeven the excess fatalities higher than the maximum expectedpreventable cervical cancer death risk by several orders often; so, the harms are definitely unacceptable. The MHLW
and the manufacturers should admit the causality of the HPV
vaccine in serious adverse reactions as soon as possible. HPV
vaccine should be withdrawn from the market and all womeninoculated with HPV vaccine should be followed up.

Page 12 ・ MED CHECK - TIP APRIL 2015 / Vol.1 No.1

References
1 - Uchide K, Kobayashi M, Hama R, Beppu H，Effect and Harmof HPV Vaccine，The Informed Prescriber (TIP) 2013：28(2)：17-27.(in Japanese) http://tip-online.org/
2 - Hama R，Incidence of consciousness loss caused by HPV
vaccination and its underlying mechanism, TIP: 2013；28(4)：67-74. (in Japanese)3 - Hama R, Tanida N，Pain/neurological symptoms afteradministration of HPV vaccine: isn’t it antiphosopholipid syndrome?
TIP 2013；28(5)：79-89 (in Japanese)
4 - Hama R, Tanida N, Risk of autoimmune diseases following HPV
vaccination: analysis by time trend. TIP: 2013；28(5)：89-99 (inJapanese)
5 - Hama R, HPV Vaccine is harmful enough to be banned. “CheckMed” 2013 (July)：No51：66-71. (in Japanese)
6 - The Check Med editorial team. HPV vaccine: Q&A “CheckMed” 2013 (Oct)：No52：23-28.
7 - Hama R, Stop using HPV vaccine: growing evidence of harm.
“Check Med” 2013 (Oct)：No52：29-43. (in Japanese)
8 - Hama R, What is adjuvant? What is HPV vaccine “Check Med”
2014(Jan)：No53：47-67. (in Japanese)
9 - The Check Med team, International Symposium on the Harmof HPV Vaccine “Check Med” 2014 (April)：No54：64-68. (inJapanese)10 - The Check Med team, “Check Med” On-line Breaking News: (inJapanese) http://www.npojip.org/contents/sokuho/1.htmla) No163 (2013.11.18：Harm of HPV vaccine: Open accessInformation (in Japanese)b) No164 (2014.1.28）：Full review of HPV Vaccine: Toxicity of
Adjuvant and adjuvant- induced Diseases (in Japanese)c) No165 (2014.1.29）: HPV Vaccine: Serious Adverse Reactions
might Occur in one or 0.5 per 100 Persons. (in Japanese)d) No166 (2014.1.29): HPV Vaccine: Do not resume active
recommendation of HPV vaccine: It’s extremely harmful (inJapanese)e) No167 (2014.2.28） International Symposium on Harm of HPV
Vaccine was Held (in Japanese)
11 - Yokota S, “I dare comment on modern medicine: my fairargument” Kanagawa Prefecture Medical Association Newsletter
2014: (2014. 8) No10: p11-12 (in Japanese)
12 - The Check Med editorial team “What it means to Suffer from
Harms of Medicines” NPOJIP 2014.10 (in Japanese)
13 - Joint Meeting of MHLW Health Science Council Immunization/
Vaccination Subcommittee Adverse Reaction Working Group andPharmaceutical Affairs and Food Sanitation Council Pharmaceutical
Safely Task Force Safety Measure Research Group (in Japanese)
http://www.mhlw.go.jp/stf/shingi/2r98520000008f2q.html#shingi127715

Joint Meetinga) Oct. 29, 2014 http://www.mhlw.go.jp/stf/shingi2/0000063390.htmlb)July 4, 2014 http://www.mhlw.go.jp/stf/shingi/0000050385.htmlc)Feb. 26,2014 http://www.mhlw.go.jp/stf/shingi/0000038488.htmld)January 20, 2014 http://www.mhlw.go.jp/stf/shingi/0000035220.html
14 - Lu B, Kumar A, Castellsagué X, Giuliano AR. Efficacy and
Safety of Prophylactic Vaccines against Cervical HPV Infection and
Diseases among Women: A Systematic Review & Meta-Analysis.
BMC Infectious Diseases 2011, 11:13
15 - Siegrist CA, Lewis EM, Eskola J, Evans SJ, Black SB. Human
Papilloma Virus Immunization in Adolescent and Young Adults:
A Cohort Study to Illustrate What Events Might be Mistaken for
Adverse Reactions. Pediatr Infect Dis J 2007;26 979-984
16 - Gee J, Naleway A, Shui I, et al. Monitoring the safety ofquadrivalent human papillomavirus vaccine: Findings from the
Vaccine Safety Datalink. Vaccine 2011:29 (46): 8279-8284
17 - Arnheim-Dahlström L, Pasternak B, Svanström H, Sparén P,
Hviid A. Autoimmune, neurological, and venous thromboembolic

adverse events after immunisation of adolescent girls withquadrivalent human papillomavirus vaccine in Denmark andSweden: cohort study. BMJ. 2013 Oct 9; 347: f5906.
18 - Kinugasa Mari, Risk and Merit of HPV Vaccine: “Genuinenessof Information on the Internet” Medical Governance Association
Mail Magazine: No1210-No1213（2014.9.19-9.20） http://medg.
jp/ (in Japanese)
19 - Niedziela N, Adamczyk-Sowa M, Pierzchała K. Epidemiology
and clinical record of multiple sclerosis in selected countries: asystematic review. Int J Neurosci. 2014 May;124(5):322-30.
20 - Osoegawa M, Kira J, Fukazawa T et al. Temporal changes
and geographical differences in multiple sclerosis phenotypes inJapanese: nationwide survey results over 30 years. Multiple Sclerosis
2009;15(2):159–73.
21 - von Kries R, Toschke AM, Strassburger K, Kundi M, Kalies
H, Nennstiel U, Jorch G, Rosenbauer J, Giani G. Sudden
and unexpected deaths after the administration of hexavalentvaccines (diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B,
Haemophilius influenzae type b): is there a signal? Eur J Pediatr.
2005 Feb;164(2):61-9. Epub 2004 Dec 16.
22 - Tango Toshiro, “Statistics for Medicine” Asakura Shoten, 1993
(in Japanese)
23 - DeStefano F, Verstraeten T, Jackson LA, et al. Vaccinations andRisk of Central Nervous System Demyelinating Diseases in Adults.
Arch Neurol. 2003. 60(4):504-509.
24 - Jefferson T, Rudin M, Di Pietrantonj C. Adverse events after
immunization with aluminium-containing DTP vaccines: systematic
review of the evidence. Lancet Infect Dis. 2004. 4(2):84-90.
25 - David MP, Van Herck K, Hardt K, et al. Long-term persistenceof anti-HPV-16 and -18 antibodies induced by vaccination with theAS04-adjuvanted cervical cancer vaccine: modeling of sustained
antibody responses. Gynecol Oncol. 2009;115(3 Suppl):S1-6

Supplementary references (for Cervarix RCTs)a) Paavonen J, Jenkins D, Bosch FX, et al. HPV PATRICIA study group. Efficacy
of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against
infection with human papillomavirus types 16 and 18 in young women: an interim
analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007 Jun
30;369(9580):2161-70. Erratum in: Lancet. 2007 Oct 20;370(9596):1414.
b) Paavonen J, Naud P, Salmerón J, et al; HPV PATRICIA Study Group. Efficacy
of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against
cervical infection and precancer caused by oncogenic HPV types (PATRICIA):
final analysis of a double-blind, randomised study in young women. Lancet.
2009 Jul 25;374(9686):301-14.. Epub 2009 Jul 6. Erratum in: Lancet. 2010 Sep
25;376(9746):1054.
c) Lehtinen M, Paavonen J, Wheeler CM et al; HPV PATRICIA Study Group.
Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater
cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised,double-blind PATRICIA trial. Lancet Oncol. 2012 Jan;13(1):89-99. Epub 2011
Nov 8. Erratum in: Lancet Oncol. 2012 Jan;13(1):e1.

Harm/benefit comparison in our first analysis [ref.1]

For the comparison between the reported proportion ofserious adverse reactions among innoculated HPV-vaccinees
and preventable cervical cancer deaths, we wrote as follows:
Among 599 serious adverse reaction reports, 95% occurred
within a week and only three (0.5%) occurred after one
month or later. Reported proportion of serious reactions
to Gardasil and to Cervarix were 9 to 11 and 26 to 29 per
100,000 persons inoculated respectively. On the other hand,maximum preventable cervical cancer deaths attributable to
HPV vaccine were expected 1.5 per 100,000 person years
in Japan (mortality is standardized by the world population).
The former are about 6 to 9 times and 17 to 23 times higher
respectively.

Plain Language summary

SGLT-2 inhibitors: inacurate
to call these“medicines”
What is diabetes? What is insulin?
What is the target of treatment?

Diabetes is NOT a simple disease in which blood sugar(glucose) levels increase. It is a disease in which insulin
secretion decreases or work poorly. As a result, variousorgan failures might occur without adequate management
but, a long normal life is still possible if the disease isproperly managed. Insulin is excreted from the pancreas andis essential for the body to work, because it maintains themetabolism of various nutrients such as sugars (carbohydrate),
lipids and proteins. Hence, if the amount of insulin excretion
decreases, the human body cannot utilise nutrients properly.
Unutilised sugar increases in the blood and various symptoms
occur: excessive thirst, overeating, drinking too much water,
confusions and other mental impairment, etc. Blood vessels
and nerves are damaged. Various organs such as the eye(especially the retina), kidney and heart deteriorate after along period of time, over several years or dozens of years.
Treatment of diabetes does NOT simply aim to “normalizet h e b l o o d s u g a r l e ve l s …… ” b u t “ t o n o r m a l i z e t h emetabolism of nutrients and to prolong life, preventing
various complications.” DO NOT CONFUSE them.
An adequate amount of nutrients especially fats andproteins necessary for one’s physical constitution (height) andactivity is essential to maintain a healthy body and a healthy
mind.
Insulin needs to be secreted especially when one eatscarbohydrates (sugars). Hence, a low carbohydrate diet may
decrease the need for insulin to be secreted and this is goodfor patients with lowered insulin secretion. Adequate exercise
is always good for health. If one cannot achieve good blood
glucose level through a low carbohydrate diet with adequate
exercise, insulin therapy may be necessary.
Other medicines for diabetes such as sulfonylureas,
metformin, alfa-glucosidase inhibitors, which delay absorptionof sugars, and other newly developed oral or injectable
hypoglycemic agents have not been proven to prolong thelife of diabetics. These are of little use and harmful to health.
Insulin is the only medicine needed by diabetics. However,even insulin can induce cancer.
SGLT-2 inhibitors are newly introduced agents for diabetes
and are used for lowering blood sugar by impairing theactivity of kidneys to reabsorb sugar. These medications
lower blood glucose but may increase dehydration, leading
to stroke, increased urinary tract infections (bladder andkidney), life-threatening skin disease and cancer. You should
avoid SGLT-2 inhibitors.

MED CHECK - TIP APRIL 2015 / Vol.1 No.1 ・ Page 13

Plain Language summary

Plain Language summary"Pylori" removal may shorten life

Harm of HPV vaccine:
Epidemiologic studies do not probe safety

Proton pump inhibitors (PPIs) are drugs which reduce acidin the stomach by inhibiting proton (hydrogen ion) pumpactivity in the acid excreting cells. These drugs are used totreat stomach and duodenum ulcers for short periods (8weeks for stomach ulcers and 6 weeks for duodenum ulcers).
These drugs are also used to remove bacteria called “pylori ”
from the stomach to prevent stomach and duodenum ulcers ,and stomach cancer.
However, PPIs increase infection from other bacteria. Oneof the most important of these bacteria is called Clostridium
difficile (C. difficile) which can cause serious enteritis, asometimes fatal condition. One of the reasons why this typeof serious infection occur is because many people have C.
difficile without exibiting symptoms, Moreover, PPIs inhibit
not only the proton pump action in stomach cells but also
another type called vacuolar proton pump (V-ATPase) which
exists in almost all cells of the body and has an important role
to maintain normal cell functions. Inhibition of the latter typeof proton pump may impair functions of various cells, such as
renal, bone, sperm and immune cells which are important foracidification of urine, bone resorption, sperm maturation andfor adequate PH maintenance.
The benefit of removal of “pylori ” in healthy carriers has tobe weighed against the harmful effects including increased
risk of infection and decide whether it may prolong life ornot. Long-term well controlled clinical trials have shownthat removal of “pylori ” in healthy carriers decreased gastriccancer incidence, but tended to increase all-cause mortality
compared with the control group.
lf you have “pylori ” in your stomach without gastric or
duodenal ulcers, “pylori ” should not be removed by PPIs.

M
C

Two HPV vaccines (Cervarix and Gardasil) have beenmarketed in Japan since 2010. More than 3 million girls were
inoculated with HPV vaccines prior to the withdrawal of arecommendation for inoculation by the Japan's Ministry of
Health, Labor and Welfare (MHLW) in May 2013.
Incidence of serious adverse reactions to Cervarix was
800 among 2.6 million girls inoculated (one in 3000 before
withdrawal of the recommendation), while the incidence
increased to 3.2% per year after the retraction, using thelatest data (3,200 cases per 100,000 person years or one
in 30 per year). This is similar to the frequency of serious
adverse events within 1.2 years after the first vaccination(annual rate of 2.8%) reported in a well-controlled clinicalstudy of Cervarix. In this study, annual incidence of serious
reactions, autoimmune diseases and death after 3.4 years
comparing with those between 1.2 and 3.4 years wasestimated as 4%, 0.63% and more than one per thousand
respectively. These incidence rates may also occur in Japan.
The epidemiologic surveys that the MHLW used as
evidence of safety have serious flaws in their methodologies.
One study confuses incidence (newly occurred disease among acertain population within a certain period of time) with prevalence (aproportion of persons having a disease among a certain population
at a certain point of time) . The other two studies have a serious

bias known as the “healthy vaccinee effects”. Those vaccinatedare usually healthier than those non-vaccinated, because thelatter group avoid vaccines due to health problems.
While there is no evidence yet that HPV vaccine decreases
mortality from cervical cancer, if we assume that the vaccine
could cut the cervical cancer mortality by half, the expected
maximum benefit would be 2.0 less deaths per 100,000
person-years. Hence, the harm experienced is overwhelmingly
greater than the expected maximum benefit.
We strongly recommend avoiding HPV vaccine.

ED

HECK

The Informed Prescriber
2015

Vol.1

No.1

Editor-in-Chief: HAMA, R. (MD)
Deputy Editor: KIMOTO, Y. (MD); TANIDA, N. (MD)Managing Editor: SAKAGUCHI, K.
Editorial Staff:JONES,M.(PhD,Statistician); AIHARA,M.(MD);NAKANISHI,T. (Pharmacist) ; OHTSU, F .(Pharmacist) ;TAKANO, Y .(MD/Pharmacist) ; YASUDA, Y. (Pharmacist)
English Editor: BOETTCHER, A. (Journalist / Communications
Specialist)

Page 14 ・ MED CHECK - TIP APRIL 2015 / Vol.1 No.1

Translators: NAKAMURA, A. ; TAKAMACHI, K.
Advisors:HONZAWA,T.MD[GP]); IWAMOTO,K.(Pharmacist);KIM,M.
(Pharmacist); MUKAI, J.(Pharmacist); SEGAWA,Y.; SUMIDA, S. (MD[Dermatologist]); TERAOKA, A. (Pharmacist) ; TOI, C. (Pharmacist)
Editorial Officers: PRAXTONE, M.; SAKAGUCHI, K.
Production Team: MATSUMOTO, K. ;UMEKI, Y. ; SAKAGUCHI,K.
Information Technology (IT): KURODA , A (Systems Engineer)
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