A worldwide yearly survey of new data

in adverse drug reactions

 A worldwide yearly survey of new data
in adverse drug reactions
Pam Magee, in Side
Pam
Effects
Magee,
of Drugs
in SideAnnual,
Effects2011
of Drugs Annual, 2011

ObservationalObservational
studies studies
Hypochlorite is veryHypochlorite
unstable, but is hypochlorous
very unstable, acid
but hypochlorous
is stable and isacid
highly
is stable
micro-and is highly micro-
bicidal, active against
bicidal,
bacteria,
activeviruses,
againstandbacteria,
fungi.viruses,
It has been
and used
fungi.inIt30
has
patients
been used
to in 30 patients to
treat venous leg ulcers
treatthat
venous
had leg
notulcers
healedthat
withhad
conventional
not healed treatment;
with conventional
10 achieved
treatment; 10 achieved
a 44% ulcer reduction
a 44%after
ulcer
3 weeks
reduction
[64c].after
The other
3 weeks20 [64
patients
c]. Thewere
otherthen
20 patients
treated were then treated
for 12 weeks; in nine
forcases
12 weeks;
therein was
nine
fullcases
healing
there
and was
in full
five healing
the ulcers
andwere
in five
reduced
the ulcers were reduced
in size by over 60%.inAll
sizethe
bypatients
over 60%. became
All thefree
patients
of pain.
became
Adversefree
effects
of pain.
were Adverse
not effects were not
reported. reported.

> Read full chapter

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Sulfur Amino
SulfurAcids
AminoandAcids
Skeletal
and Mus-
Skeletal Mus-
cle cle
Isabelle Papet, ... Isabelle
IsabelleSavary-Auzeloux,
Papet, ... IsabelleinSavary-Auzeloux,
Nutrition and Skeletal
in Nutrition
Muscle,
and2019
Skeletal Muscle, 2019

General RolesGeneral
of Taurine,
Roles
Hydrogen
of Taurine,
Sulfide,
Hydrogen
and Sulfate
Sulfide, and Sulfate
Molecules issued from
Molecules
the degradation
issued from
ofthe
cysteine
degradation
and a fortiori
of cysteine
fromand
methionine
a fortiori from methionine
are not only by-products
are notbut
only
also
by-products
are metabolic
but also
actors.
are metabolic actors.

Taurine is an antioxidant,
Taurineitisneutralizes
an antioxidant,
hypochlorous
it neutralizes
acid,hypochlorous
a reactive species
acid,pro-
a reactive species pro-
duced by neutrophils.
ducedIt isbyalso
neutrophils.
involved inIt conjugation
is also involved
reactions
in conjugation
playing areactions
role playing a role
in elimination of toxins,
in elimination
metabolism of toxins,
of lipids
metabolism
(via bile acid
of lipids
conjugation),
(via bile acid
activity
conjugation), activity
of glycolipids, to name
of glycolipids,
a few. Moreover,
to nametaurine
a few. Moreover,
modulates taurine
basic processes,
modulates such
basic processes, such
as osmotic pressure,as cation
osmotic homeostasis,
pressure, cation
enzyme homeostasis,
activity, receptor
enzymeregulation,
activity, receptor
cell regulation, cell
development, and development,
cell signaling [59–62].
and cell signaling [59–62].

H2S has been identified

H2S hasas abeen
“gaseous”
identifiedsignaling
as a “gaseous”
moleculesignaling
such as nitric
molecule
oxidesuch
(NO)as nitric oxide (NO)
and carbon monoxide and (CO)
carbon [55].
monoxide
It is also (CO)
recognized
[55]. It as
is also
a cytoprotectant
recognized asplayer
a cytoprotectant
[63]. player [63].
At physiological pH,At about
physiological
80% of pH, totalabout
free soluble
80% ofHtotal2S isfree
present
soluble
as HS
H2−S, 20%
is present as HS−, 20%
as neutral (H2S) andas there
neutralis essentially
(H2S) and there
no dianionic
is essentially
S2− innobiological
dianionicfluids
S2− in
[64].
biological fluids [64].
There are also two There
formsareof storage
also twowithformsproteins
of storage
[65]. with
Intracellular
proteinsconcentrations
[65]. Intracellular concentrations
of total free pool are
of only
total 10
freenM–3
pool μMare only
due to10rapid
nM–3degradation
μM due to rapidunderdegradation
aerobic under aerobic
conditions [65,66].conditions
A recent blooming
[65,66]. Aliterature
recent blooming
reports theliterature
implication
reports
of Hthe2Simplication
in of H2S in
a variety of physiological functions, notably in vascular function and neurological
systems among many others [55]. Mechanisms of action and molecular targets of
H2S are incompletely defined, and investigations are complicated by methodological
limitations regarding accurate measurement of H2S and metabolic interrelations
between various sulfur-containing molecules [55,67–70]. Some of the physiological
responses attributed to H2S have recently found to be rather induced by polysulfides
(H2Sn) [65].
 a variety of physiological functions, notably in vascular function and neurological
systems among many others [55]. Mechanisms of action and molecular targets of
H2S are incompletely defined, and investigations are complicated by methodological
limitations regarding accurate measurement of H2S and metabolic interrelations
between various sulfur-containing molecules [55,67–70]. Some of the physiological
responses attributed to H2S have recently found to be rather induced by polysulfides
(H2Sn) [65].

Free SO42− pools are Free

notSOonly
42− pools
suppliedare mainly
not onlybysupplied
the catabolism
mainly of bycysteine
the catabolism
[71] butof cysteine [71] but
also by the transport-mediated
also by the transport-mediated
intestinal absorption intestinal
of SO42−absorption
, the transport-mediat-
of SO42−, the transport-mediat-
ed renal reabsorption ed renal
of SOreabsorption
42−, the degradation
of SO42−of, the
sulfur-containing
degradation of molecules,
sulfur-containing
and molecules, and
the activity of sulfatases
the activity
[72]. SO
of 42−
sulfatases
is converted
[72]. SO
to 342−-phosphoadenosine
is converted to 3 -phosphoadenosine
5 -phos- 5 -phos-
phosulfate (PAPS) [73]phosulfate
that is the
(PAPS)
universal
[73] that
sulfonate
is the universal
donor implicated
sulfonatein donor
various
implicated in various
sulfotransferase reactions
sulfotransferase
[72]. PAPS, reactions
the activated
[72]. PAPS,
form theof SO
activated
42−, is required
form of in SO(1)
42−, is required in (1)

the inactivation of thyroid

the inactivation
hormones, of thyroid
catecholamines,
hormones, andcatecholamines,
steroid hormones; and steroid
(2) the hormones; (2) the
structure of sulfolipids,
structure
glycosaminoglycans,
of sulfolipids, glycosaminoglycans,
and glycoproteins;and (3) the
glycoproteins;
elimination(3) the elimination
of bile acids; (4) theofposttranslational
bile acids; (4) themodification
posttranslational
of tyrosine-containing
modification of tyrosine-containing
secretory secretory
proteins; (5) the activation
proteins;of(5)pharmacological
the activation ofdrugs;
pharmacological
and (6) the detoxification
drugs; and (6) the detoxification
through phase II conjugation
through phase reaction
II conjugation
of xenobiotics
reaction
and of pharmacological
xenobiotics anddrugs pharmacological drugs
[74–76]. In the detoxification
[74–76]. In process
the detoxification
of paracetamol,
process sulfonation
of paracetamol,
(sulfation)
sulfonation
is a (sulfation) is a
high-affinity but low-capacity
high-affinityreaction
but low-capacity
that is saturable
reaction when
that increasing
is saturabledosewhen [77].
increasing dose [77].
This feature contributes
This feature
to paracetamol
contributestoxicity
to paracetamol
consecutivetoxicity
to overdoses
consecutive
[6]. to overdoses [6].
environment. These fragments were shown to be much smaller than fungal conidia.
It is possible that these fragments also carry mycotoxins and that they contribute to
fungal contamination of contents. The cleaning techniques discussed above may be
effective against fungal fragments, but this remains to be examined.
environment. These fragments were shown to be much smaller than fungal conidia.
It is possible that these fragments also carry mycotoxins and that they contribute to
fungal contamination of contents. The cleaning techniques discussed above may be
effective against fungal fragments, but this remains to be examined.
endoscopy.Administration of water has also been recommended. However,
sulfuric acid mixed with water generates a substantial amount of heat. To
minimize the risk of local build up of heat in the stomach, moderate quantities
of water are recommended (250–500 mL).Early endoscopy is recommended
to evaluate the degree of damage to the gastrointestinal tract and to de-
termine if surgical interventions are required.Aspiration and associated lung
injuries should always be suspected until definitively disproven.The formation
of strictures in the upper digestive tract is the norm following significant acid
ingestions.
 endoscopy.Administration of water has also been recommended. However,
sulfuric acid mixed with water generates a substantial amount of heat. To
minimize the risk of local build up of heat in the stomach, moderate quantities
of water are recommended (250–500 mL).Early endoscopy is recommended
to evaluate the degree of damage to the gastrointestinal tract and to de-
termine if surgical interventions are required.Aspiration and associated lung
injuries should always be suspected until definitively disproven.The formation
of strictures in the upper digestive tract is the norm following significant acid
ingestions.
Eye injuriesIn general,
Eye injuriesIn
acid injuries
general,
to theacideye injuries
tend to beto the
lesseyesevere
tendthan
to be less severe than
alkali injuries. However,
alkali injuries.
they canHowever,
be very painful.Specialized
they can be very painful.Specialized
equipment (e.g., equipment (e.g.,
a Morgan lens) may a Morgan
be requiredlens)eye
may
irrigation.
be requiredThe eye
affected
irrigation.
eye should
The affected
be eye should be
irrigated with 2 L of
irrigated
irrigation
withfluid
2 Lover
of irrigation
30–60 minutes
fluid overor until
30–60the minutes
pH of or until the pH of
the irrigation solution
the irrigation
is 7.4.Thesolution
cornea, sclera,
is 7.4.The
andcornea,
conjunctiva
sclera,should
and conjunctiva
be should be
thoroughly examined thoroughly
for evidence
examined
of damage
for evidence
(includingof damage
fluorescein (including
uptake).-
fluorescein uptake).-
Chemical eye injuries
Chemical
are commonly
eye injuries
genuine
are commonly
ophthalmic genuine
emergencies
ophthalmic
and emergencies and
specialist evaluation
specialist
as soonevaluation
as possibleasissoon
recommended.
as possible is recommended.
Clinically significant
Clinically
exposures significant
to chlorine
exposures
and/or to chloramine
chlorine and/or
gas (particularly
chloramine gas (particularly
in enclosed spaces)Patients
in enclosed exposed
spaces)Patients
to large concentrations
exposed to large in an
concentrations
enclosed in an enclosed
environment and patients
environment with underlying
and patients respiratory
with underlying
or cardiovascular
respiratorydis-
or cardiovascular dis-
ease should be hospitalized
ease should andbemonitored
hospitalized forand
delayed
monitored
respiratory
for delayed
effects respiratory effects
irrespective of theirirrespective
initial condition.
of theirA initial
common condition.
mistakeA is common
to discharge
mistake
suchis to discharge such
patients too early in
patients
the course
too early
of theintoxicoses.Historical
the course of the toxicoses.Historical
recommendations recommendations
that patients be nebulized
that patients
with sodium
be nebulized
bicarbonate
with sodium
have been
bicarbonate
demonstrated
have been demonstrated
to be ineffective, and
to beat worse,
ineffective,
may and
exacerbate
at worse, respiratory
may exacerbate
damagerespiratory
by causingdamage by causing
chemical pneumonitis.Airway
chemical pneumonitis.Airway
security is paramount security
due tois paramount
the risk of laryn-
due to the risk of laryn-
gospasm and laryngeal
gospasm edema.
andItlaryngeal
is alwaysedema.
better to
It intubate
is always too
better
early
to than
intubate too early than
too late during thetoo
clinical
late during
course.Short-acting
the clinical course.Short-acting
2-agonist bronchodilators
2-agonist bronchodilators

(e.g., salbutamol, clenbuterol)

(e.g., salbutamol,
plus supplemental
clenbuterol) plus
oxygen supplemental
may be required
oxygentomay be required to
counteract the bronchoconstrictor
counteract the bronchoconstrictor
effects.Ventilation effects.Ventilation
may be required, but may be required, but
is often not available
is often
in veterinary
not available
practice.Conservative
in veterinary practice.Conservative
fluid managementfluid management
(i.e., avoidance of over-hydration)
(i.e., avoidance of hasover-hydration)
been historically hasrecommended
been historicallyin the
recommended in the
treatment of the acute
treatment
respiratory
of thedistress
acute respiratory
syndrome.distress
Recent syndrome.
human dataRecent human data
suggest that conservative
suggestfluid that management
conservative fluid doesmanagement
not decrease does the death
not decrease the death
rate. However, conservative
rate. However,
fluid management
conservative fluid was associated
management withwas
improved
associated with improved
oxygenation and lessoxygenation
severe nonpulmonary
and less severe effects.
nonpulmonary
It should beeffects.
noted Itthatshould be noted that
conservative fluid management
conservative fluid doesmanagement
not mean thedoes induction
not mean
of dehydration;
the induction of dehydration;
rather it means therather
maintenance
it meansofthe anmaintenance
even fluid balance.The
of an evenuse fluidofbalance.The
anti-in- use of anti-in-
flammatories suchflammatories
as corticosteroids,
such as statins,
corticosteroids,
and macrolide statins,
antibiotics
and macrolide
for antibiotics for
treatment of the acute
treatment
respiratory
of thedistress
acute respiratory
syndrome distress
is controversial.
syndrome There
is controversial. There
is equivocal evidence
is equivocal
that corticosteroids
evidence that decrease
corticosteroids
mortality.decrease
However,mortality.
there However, there
is limited evidence that corticosteroids may reduce lung and other organ
injury, although the effects are small.Antioxidants such as n-acetyl cysteine and
nebulized surfactant (recombinant surfactant protein C, synthetic surfactants,
reconstituted animal surfactants) are often administered for the treatment of
the acute respiratory distress syndrome. Despite promising experimental data,
the clinical effectiveness of these treatments is often limited.
is limited evidence that corticosteroids may reduce lung and other organ
injury, although the effects are small.Antioxidants such as n-acetyl cysteine and
nebulized surfactant (recombinant surfactant protein C, synthetic surfactants,
reconstituted animal surfactants) are often administered for the treatment of
the acute respiratory distress syndrome. Despite promising experimental data,
the clinical effectiveness of these treatments is often limited.
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Free andFree
Combined
and Combined
ChlorineChlorine
Nicholas F. Gray, inNicholas
Microbiology
F. Gray,
ofin
Waterborne
Microbiology
Diseases
of Waterborne
(Second Edition),
Diseases2014
(Second Edition), 2014

Free ChlorineFree Chlorine

Chlorine gas rapidly
Chlorine
reacts with
gas rapidly
water molecules
reacts withinwater
an aggressive
moleculesreaction
in an aggressive
to form reaction to form
hypochlorous acid hypochlorous
(HOCl) and hydrochloric
acid (HOCl)acid
and(HCl;
hydrochloric
Eq. 31.1).
acid
The(HCl;
former
Eq. is31.1).
a The former is a
weak acid which rapidly
weak acid
dissociates
which rapidly
to give dissociates
hypochloritetoions
give (OCl
hypochlorite
−) with a chemical
ions (OCl−) with a chemical
equilibrium developing
equilibrium
between developing
the associated
betweenandthe
unassociated
associated forms
and unassociated
(Eq. 31.2). forms (Eq. 31.2).
Both HOCl and OCl Both
− have
HOCl
disinfection
and OCl−properties
have disinfection
but the acid
properties
only dissociates
but the acidunder
only dissociates under
alkaline conditions.alkaline
The hydrochloric
conditions.acid
Thealso
hydrochloric
dissociates
acid
resulting
also dissociates
in a reduction
resulting
in in a reduction in
both pH and the alkalinity
both pHof and
thethe
water
alkalinity
[Eq. 31.3].
of the water [Eq. 31.3].

[31.1] [31.1]

[31.2] [31.2]

[31.3] [31.3]

The degree of dissociation

The degree of hypochlorous
of dissociationacidof hypochlorous
is pH dependentacidbeing
is pHgradually
dependent being gradually
suppressed as the suppressed
pH falls. At aaspHthe<pH
5.0 falls.
then Atapproximately
a pH < 5.0 then
100% approximately
of the chlorine
100% of the chlorine
is in HOCl form which
is in HOCl
falls toform
50% which
at pH falls
7.5, while
to 50%at at
pHpH
> 9.0
7.5,100%
while of
at chlorine
pH > 9.0is100% of chlorine is
present as OCl− (Table
present
31.2).
asHypochlorous
OCl− (Table 31.2).
acidHypochlorous
has much faster
acid
reaction
has muchratesfaster
thanreaction rates than
hypochlorite, beinghypochlorite,
approximately being
80 times
approximately
more effective.
80 timesTherefore,
more effective.
chlorination
Therefore, chlorination
is most effective atisa most
slightly
effective
acidic pH
at a (pH
slightly
< 7.0).
acidic
Temperature
pH (pH < also
7.0).has
Temperature
a small also has a small
effect on the dissociation
effect on of the
HOCldissociation
causing the of HOCl
reactioncausing
to occur
theatreaction
slightlytohigher
occur at slightly higher
pH values at lowerpH temperatures.
values at lower
Chlorine
temperatures.
will react Chlorine
with any will
reducing
react with
agentsanyorreducing agents or
organic matter in the
organic
treated
matter
water,
in so
thethat
treated
free water,
chlorine soresiduals
that free may
chlorine
not remain
residuals may not remain
for very long withinforthe
very
distribution
long within network.
the distribution
The decaynetwork.
rate of free
Thechlorine
decay ratein of
thefree chlorine in the
distribution networkdistribution
follows a first
network
orderfollows
kinetics.
a first
In practice,
order kinetics.
the cleaner
In practice,
the waterthe cleaner the water
the longer the residual
the longer
effect lasts.
the residual
Hypochlorite
effect lasts.
ions rapidly
Hypochlorite
react with
ionsthe
rapidly
photons
react with the photons
in sunlight producing
in sunlight
oxygen,producing
chlorite and oxygen,
chloride.
chlorite
The rate
and of
chloride.
this reaction
The rateis very
of this reaction is very
pH dependent withpH thedependent
half life ofwith
freethe
chlorine
half life
falling
of free
fromchlorine
50 minutes
fallingatfrom
pH 650tominutes at pH 6 to
10 minutes at pH 810(Black
minutes
andat Veatch
pH 8 Corporation,
(Black and Veatch 2010).Corporation, 2010).

Table 31.2. Variation

Table
of the
31.2.
Percentage
Variation of Hypochlorous
the PercentageAcid
of Hypochlorous
(HOCl) with Temper-
Acid (HOCl) with Temper-
ature and pH as a Percentage
ature and pH of as
Free
a Percentage
Chlorine inofDrinking
Free Chlorine
Water in Drinking Water

HOCl (%) HOCl (%)

pH
impaired in killing Candida spp. or Aspergillus spp. in vitro despite the fact that most
patients with MPO deficiency do not develop significant fungal infections. This
suggests that the mucosal barrier to fungal infection is independent of MPO activity
and is able to prevent invasive infection.
and major basic protein (MBP) despite the presence of messenger RNA (mRNA)
transcripts for these proteins. Few patients have been reported to have survived
beyond adolescence except for those with a milder dominant form. Bone marrow
transplantation should be considered early in the course of the disease.
 and major basic protein (MBP) despite the presence of messenger RNA (mRNA)
transcripts for these proteins. Few patients have been reported to have survived
beyond adolescence except for those with a milder dominant form. Bone marrow
transplantation should be considered early in the course of the disease.

Key Concepts Key Concepts

Specific GranuleSpecific
Deficiency
Granule
(SGD)Deficiency (SGD)
•SGD is caused by promyelocyte–myelocyte
•SGD is caused by promyelocyte–myelocyte
transition block as transition
a result of block
a mutation
as a result of a mutation
in the C/EBP gene.•Absence
in the C/EBPof secondary
gene.•Absence
granule
of secondary
proteins, and
granule
a selective
proteins,
lossand
of a selective loss of
the primary granule
thedefensins
primary granule
are the pathological
defensins arefindings
the pathological
in SGD granulocytes.•-
findings in SGD granulocytes.•-
The prognosis is very
Thepoor
prognosis
in recessive
is veryforms
poor in
of recessive
SGD. forms of SGD.
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Animal Models
Animalof
Models
Systemic
of Systemic
SclerosisSclerosis
Toshiyuki Yamamoto,
Toshiyuki
in Animal
Yamamoto,
Models for
in Animal
the Study
Models
of Human
for theDisease,
Study of2013
Human Disease, 2013

HOCl-InducedHOCl-Induced
Murine Scleroderma
Murine Scleroderma
Recently, local injections
Recently,
of agents
local injections
generating of agents
variousgenerating
types of ROS various
inducedtypes
skin
of ROS induced skin
sclerosis in mice. Daily
sclerosis
intradermal
in mice. injections
Daily intradermal
of hypochlorous
injectionsacidof hypochlorous
(HOCl) induceacid (HOCl) induce
skin and lung fibrosis,
skin kidney
and lung damages,
fibrosis,and kidney
serum damages,
topoisomerase-1
and serum(Topo-I)topoisomerase-1
an- (Topo-I) an-
tibody production tibody
in Balb/cproduction
mice.104 On in Balb/c
the other
mice. hand,
104 On local
theinjections
other hand, of agents
local injections of agents
generating peroxynitrite
generating
anions peroxynitrite
(ONOO-) induced anions limited
(ONOO-) skin,
induced
but not limited
lung, fibrosis
skin, but not lung, fibrosis
and anti-CENP-B antibody
and anti-CENP-B
production. antibody
As wellproduction.
as bleomycin, As well
thoseasagents
bleomycin,
are capa-
those agents are capa-
ble of producing ROS,ble of
which
producing
induces ROS,
phenotypic
which induces
differentiation
phenotypic intodifferentiation
myofibroblastsinto myofibroblasts
and enhances the production
and enhances of type
the production
I collagen, possibly
of type I via
collagen,
the phosphorylation
possibly via theofphosphorylation of
extracellular signal-related
extracellular
kinasesignal-related
1/2 (ERK1/2)kinaseand activation
1/2 (ERK1/2) of the
andRas activation
pathway.ofInthe Ras pathway. In
the HOCl-inducedthe fibrosis
HOCl-induced
model, thefibrosisoverproduction
model, the of overproduction
ROS activates ADAM-17,of ROS activates ADAM-17,
a protease involveda inprotease
NOTCH involved
cleavage, in NOTCH
suggesting cleavage,
that thesuggesting
NOTCH pathway that theisNOTCH pathway is
activated.105 In thisactivated.
model system,
105 In this
skinmodel
fibrosis
system,
is ameliorated
skin fibrosis by sunitinib
is ameliorated
106 andby sunitinib106 and

arsenic trioxide.107 arsenic

Some oftrioxide.
the agents107 Some
that induce
of the agents
DNA injury
that induce
and ROS DNA production
injury and ROS production
exert various effects exert
on endothelial
various effects cellsonand
endothelial
fibroblasts, cells
as and
well fibroblasts,
as cause immuneas well as cause immune
imbalance and mediator
imbalance
secretion,
and mediator
leading to secretion,
dermal sclerosis.
leading to dermal sclerosis.

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