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Phase I Study of a Topical Skin Protectant Against Chemical Warfare Agents

  • The Faculty of Medicine, The Hebrew University, Jerusalem, Israel


Vesicants and some nerve agents penetrate exposed skin, mainly through the sensitive integration areas of the personal protective equipment. Therefore, improving dermal barrier with a topical agent should reduce the threat of exposure. A topical skin protectant lotion (IB1) was developed to improve protection against chemical warfare agents. Preclinical studies in several animal models have proven the protective efficacy of IB1. Here we present the results of a randomized placebo-controlled, double-blind phase I clinical study, performed with 34 healthy volunteers. The study tested the safety of repeated applications, including ruling out transdermal permeation of magnesium, which may lead to a dangerous blood magnesium level, since the lotion contains magnesium sulfate. Other objectives included detection of dermatological adverse effects, assessment of application convenience, and effect on daily activities. Importantly, no serious adverse effects were recorded and the lotion did not interfere with daily tasks. There were no significant differences in magnesium levels between the placebo and the study groups in any of the applications. No toxic levels of magnesium were found in either group. We conclude that IB1 is probably safe, easily self-applied, and does not cause any significant inconvenience. Therefore, IB1 can be considered as an adjunctive chemical, biological, and radio-nuclear (CBRN) protective aid to field soldiers.
MILITARY MEDICINE. 174. 1:47. 2009
Phase I Study of a Topical Skin Protectant Against
Chemical Warfare Agents
Major Arik
Major Amir Krivoy*; Major Aviv
Captain Eyal Robenshtok*t;
Col Ariel Hourvitz*; LTC
Dushnitsky*; Leut Gal Marker§
ABSTRACT Vesicants and .some nerve agents penetrate exposed skin, mainly through the sensitive integration areas
of the personal protective equipment. Therefore, improving dermal harrier with a topical agent .should reduce the threat
A topical skin protectant lotion (IBI
was developed lo improve protection against chemical warfare agents.
Preclinical studies in several animal models have proven the protective efficacy of IBI. Here we present the results of
a randomized placebo-controlled, double-hlind phase I clinical study, performed with 34 healthy volunteers. The study
tested the safety of repeated applications, including ruling out transdemial permeation of magnesium, which may lead
to a dangerous blood magnesium level, since the lotion contains magnesium sulfate. Other objectives included detec-
tion of dermalological adverse effects, assessment of application convenience, and effect on daily activities. Importantly,
no serious adverse effects were recorded and the lotion did not interfere with daily lasks. There were no significant
differences in magnesium levels between the placebo and the study groups in any of the applications. No toxic levels of
magnesium were found in either group. We conclude that IBI is probably safe, easily self-applied, and does nol cause
any significant inconvenience. Therefore. IBl can be considered as an adjunctive chemical, biological, and radio-nuclear
(CBRN) protective aid to field soldiers.
SuHur mustard is a potetit vesicant that penetrates the human
skin easily and although blisters appear within hours after
exposure, the molecular damage occurs within minutes.'"^
Despite continuing efforts there are still no antidotes avail-
Several nerve agents (e.g., VX) have the ability to
penetrate the human skin, thus exerting their toxic effects. VX
specifically is considered as one of the most potent chemical
warfare agents (CWAs).''' Current chemical, biological, and
radio-nuclear (CBRN) personal protection equipment includes
a mask, protective clothing, gloves, and overboots. Any pene-
tration of
above mentioned CWAs through gaps in the pro-
tective equipment entails a potential life-threatening risk.
A topically applied pretreatment may act as a dermal barrier,
preventing the absorption of these agents through the skin and
thus their respective toxicity.'" Such skin protectant may serve
as an additional means of protection in conjunction with other
physical protection components. Towards this end, the primary
application areas should include the integration areas of the per-
sonal protective equipment, i.e., the neck, armpits, groin, waist,
wrists, and ankles, which arc also considered to be relatively
sensitive skin areas.'-' The "topical skin protectant" strategy
has been adopted by several countries so far, including Israel.'"
*CBRN Medicine Branch. Medical Corps. Israel Defense Forces. Tel
Hashomer. Israel.
f.Sarru Children's Hnspifal. Sheba Medical Center. Tel Hashomer. Israel.
^Internal Medicine E, Rabin Medical Center. Bellinson Campus. Petach-
Tikva. Israel.
§Sheba Cancer Research Center. Sheba Medical Center. Tel Hashomer.
This manuscript was received for review in Oclober 2007. The revised
manuscript was accepted for publication in September 2008.
Reprint & Copyright © by Association of Military Surgeons of
a topical skin protectant resistant to CWAs that
was developed at the Israel Institute for Biological Research
was successfully tested in various animal models."^
Using the well-established primary skin irritation Draize
test," the protectant was demonstrated to be nonirritating
in guinea pigs and in rabbits. No adverse dermatotogical
or systemic effects were found in a long-term toxicologi-
cal study in pigs following an overdose application of the
protectant (covering >209'c of the skin surface, applied three
times per day for 2 weeks). Evaluation included a clinical
follow-up for I month, blood and urine biochemistry, includ-
ing magnesium (Mg) levels, and pathology. No detectable
levels of the protectant ingredients were found in blood
and urine during the entire monitoring period.'' Also, blood
and urine Mg levels were not increased. Irritation and sen-
sitivity tests were performed on 50 human volunteers (U
39 females; 10 at the ages of 18-35 years, 14 at the
ages of 36-45, 26 at the ages of 46-65) and were not found
to be associated with any skin irritation or with any allergic
Here we tested the medical safety of repeated topical
application of the IBI lotion in a randomized placebo-
controlled double-blind phase
clinical study in young healthy
volunteers. Since the lotion includes a relatively high content
of magnesium sulfate, potential changes in serum Mg
levels were monitored, as well as other hematological and
biochemical parameters, local dermatological adverse effects,
and convenience of use.
The study was approved by the review board of the Israeli
Defense Force's (IDF) Medical Corps and was conducted
MILITARY MEDICINE, Vol. 174. January 2009
Phase I Study of a Topical Skin Protectant Against Chemical
according to the Declaration of Helsinki. All volunteers gave
their written informed consent.
Preiiminary Application Test
To determine ihe amount of IB
lotion needed for each appli-
cation, an application test was performed before the main
study. In this preliminary study 10 volunteers received small
glass vials containing 20 m! of the IB
and were asked to
cover relevant areas as described in Figure 1. The applica-
tion was performed in the presence of the researchers. After
application, the remaining lotion was weighed. On average,
-10 ml (containing 0.37 g of Mg) were required to cover all
relevant areas, and this amount was thus determined as the
experimental dose.
Volunteers were recruited from a medic's course in the
IDF's military medical school. Inclusion criteria allowed
only healthy soldiers with normal physical examination,
normal baseline complete blood count, liver function tests,
and renal function tests to participate. Soldiers with any
chronic or acute disease (especially dermatological dis-
eases) or receiving any medical treatment were excluded.
This excluded soldiers with asthma, atopic dermatitis, previ-
ously known allergy, allergic rhinitis, allergic conjunctivitis,
sun burns, skin lesions at the application areas, and soldiers
that for any reason could not replace contact lenses with
eyeglasses. Every volunteer had the right to stop participa-
tion at any time during the study. In addition, each volunteer
tilled and signed an informed consent form and a medical
Blinding Procedures
The study was designed as a randomized placebo-controlled
double-blind study. The
and the placebo lotions were pre-
pared at the IIBR and were coded by medical personnel at the
IDF's Medical Corps, who were not involved in any other part
experiment, including design, performance, or analysis.
Codes were locked throughout the experiment. The research-
who enrolled the volunteers, drew the blood, took vital
examined the volunteers, and were present in every
application, as well as a dermatologist, were blinded to the
lotion composition throughout the experiment until after al!
analyses were completed. Coding was revealed only at the end
of the study by the same personnel that coded them before the
The placebo was the vehicle of the IBl lotion,
ing of 87% glycerin (Merck. Israel) and \3% Aqua with-
out any magnesium. Both placebo and IBl lotions were
indistinguishabiy odorless, colorless, and with the same
consistency. Both were supplied in identical vials. The
researchers received a single box containing batches of
coded vials that were randomly assigned to the volun-
teers during the preparation day of the study (see below
"Experimental Protocol"). Each volunteer was assigned
one vial per application.
Experimental Protocol
A preparation day preceded the actual study by
week. Study
protocol included 4 consecutive days in which a total of
nine applications were carded out, once every 8 hours.
The preparation day included signing an informed consent
form, full medical examination, assigning the coded batches
to the volunteers, and obtaining baseline blood tests (base-
line Mg levels, complete blood count, renal functions, and
liver functions). The dosing schedule was defmed on the
basis of the pre-clinical experiments.^ The lotion was applied
on six body areas: the neck, axillae, waist, groin, wrists,
and ankles (Fig. 1). Volunteers were instructed to evenly
apply the lotion on these areas and use all 10 ml supplied.
All application sessions were performed in the presence of
the researchers to verify that all of the volunteers followed
the instructions by marking relevant checklists and draw-
Volunteers washed their hands after every application,
and only after several minutes during which the lotion was
absorbed into the skin surface did they re-dress. Worth not-
ing, the vials were collected by the researchers after each
Complete blood counts and liver function tests were
obtained in baseline and poststudy assessments. The baseline
test was required for inclusion and exclusion criteria. Further,
since the IB
lotion contains magnesium sulfate, renal func-
tion tests were taken as baseline and at the end of the study,
and blood Mg levels were monitored daily to verify that repet-
itive IBl application does not lead to a dangerous increase.
Because of the diurnal changes in Mg levels.'- '^ blood sam-
ples were drawn at the same time every day between 12:30pm
except for the baseline tests, which were obtained
between 10:30am and 11:00am. Ba.seline test results were
used for inclusion/exclusion of candidates. Hence, a total of
four blood samples were obtained from each volunteer. The
first and the last included a complete blood count, plasma Mg
level (total serum level), and liver and renal functions. Two
additional samples for plasma Mg levels were obtained from
each volunteer on days 2 and 3. Bloud samples were trans-
ferred immediately in a chilled receptacle to a medical labora-
tory facility adjacent to the base for analysis.
The volunteers were allowed to have one shower a day,
before the night application. No restrictions on any activ-
ity, including physical trainings, or on any clothing, includ-
ing uniforms, were placed on the voiunteers. Each volunteer
was fully examined by a dermatologist every day. The aim of
this examination was to identify any topical adverse effects
consistent with either allergic contact dermatitis or other local
toxic dermal effect. These were documented in a daily chart,
including an image similar to Figure 1, on which the exact
area involved could be marked.
Each volunteer filled out a daily questionnaire concerning
adverse effects. At the end of the study they all filled out a
48MILITARY MEDICINE, VtiL 174, January 200*-)
Phase I Study of a
Skin Protectant Against Chemical
FIGURE 1. Areas of lotion application.
second questionnaire on the influence of the lotion on daily
activities and their comments about the product (data not
The minimal number of subjects for the study was decided on
the basis of the following considerations: significance level
(a) 0.05; statistical power (\-ß) 0.8; anticipated effect size
(/-) 0.4. The minimal number accordingly was calculated to
be 22
( 11
in eacb group); however, since several dropouts were
expected, the study was started with 51 subjects (of which 17
indeed dropped out).
Statistical analyses were performed using SAS for Windows
version 9.1 (SAS Institute. Inc. Cary. NC). Normality of vari-
ables distribution was tested with the Smimov-Klimigorov
test. Plasma Mg levels of the two groups (ÏB1 lotion and pla-
cebo) were compared for each day of lotion application with
the Mann-Whitney nonparametric test. In addition, differ-
ences between Mg levels at each stage and the baseline lev-
els were calculated and compared between the two groups.
Analysis of variation with repeated measures was fitted for
each group, using Proc Mixed in SAS. Statistical significance
was set at 0.05. Data are shown as mean (±SD).
Of 130 soldiers approached, only 51 had volunteered. After
screening, 2 volunteers were excluded because of a history of
other volunteers were diagnosed with mild anemia at
the baseline complete blood count
iO.2 mg/dL and 10,6 mg/
I volunteer had a high bilirubin level (3.2 mg/dL), and 1
volunteer had a relatively high baseline Mg level (2.9 mg/dL).
The remaining 45 volunteers were randomized for treatment
groups. During the study, an additional 2 volunteers dropped
out because of acute tonsillitis with fever that appeared on the
second and third days of the study, and an additional 9 volun-
teers dropped out of the study at various stages because of non-
medical reasons according to their request. The 34 volunteers
who completed the full study protocol were ages 18-20 (mean
18.9 ± 0.7). Decoding revealed that
volunteers received the
IBl and 13 received placebos; 26 males (17 in the IBI group,
9 in the placebo group) and 8 females (4 in each application
The effect of gender on the results could not be mea-
sured because of small sample size.
No serious adverse effects were reported throughout the
study. Forty percent of the male volunteers in the IBI group
and 60% of the male volunteers in the placebo group reported
a short-lasting (up to 30 minutes) burning sensation when
applying the lotion after shaving, with no residual or apparent
dermal irritation upon examination by the dermatologist and
no pathological findings in their daily medical examinations.
No significant differences were found in the complete blood
counts between baseline and poststudy samples, except for a
slight increase in the white blood count, which was observed
in both groups (Table I). The mild increase was statistically
significant in the placebo group (;;-value = 0.04) and showed
a strong trend in the IBI group (p-value = 0.06). There were
no significant differences among renal and liver function tests
between the baseline and the poststudy (Table I).
After completion of the experimental protocol all volun-
teers reported that there was no interference with any daily
activity or performance, except for very mild interference
in wearing clothing and performing power drills, which was
reported by the volunteers in the IBI group mainly (Table II).
However, these interferences did not seem to impair the
soldiers' overall physical performance and hence may not
have any practical implication. All volunteers stated that the
instructions were clear and simple, there was no need for
buddy aid, and that it had no effect on their ability to concen-
trate during lectures (Table II).
Blood Mg levels were within the normal range in all sam-
ple points in both groups (1.53 mg/dL-2.6 mg/dL). except
for two sporadic samples from two different volunteers in
the IBI group (2.9 mg/dL in the third sample in one volun-
teer and 2.7 mg/dL in the fourth sample in the other). No
significant differences in Mg levels were found between
the placebo group and the IB
group in any of the tested
time points (Table III). Individual analysis of each volunteer
did not reveal any clinically significant change over time in
the Mg levels (data not shown). Differences between mean
Mg levels at each time point and ba.seline levels were calcu-
lated and compared between the two groups. The differences
were found to be insignificant (Table III). Of note, analysis
of variation with repeated measurement revealed that Mg
levels on day I were significantly lower than other measure-
ments in the same group in both placebo and IBI groups
(/i-value < 0.001 and /j-value < 0.01, respectively). However,
these differences were very small and within the normal
Mg range.
January 2009
Phase I Study of a
Skin Protectant Against Chemical
Placebo (.N= 13) Baseline
IBl(Af=21) Baseline
Renal Functions
Various Hematological and Biochemtcal Parameters
Liver Functions
Complete Blood Count
The mean values of
entire group for each of
various parameters are shown, as indicated. Results are presented for baseline blood test and for poststtidy blood
test, as well as the /»-value of a paired Student's /-test. The units used were: creatinine, mg/dL: urea, mg/dL: bilirubine, mg/dL; SGOT, lU/L; SGPT, lU/L; Hb.
g/dL; WBC. K/microL: PLT, K/microL; neutrophiles(neut). montxrytes (mono), lymphocytes (lymph), and eositiophils (eos), percentage out of white blixid cells.
TABLE II. No Signiftcant Effect of Lotion on Everyday Life
On what level of ditViculty would you define the
application of the lotion?
How much help was needed for the application?
Were there any areas that were more difficult to
apply than others?
Estimate the time needed to complete the whole
Wiis the application appalling?
Were the instructions clear?
Were there signs of irregularities
(liquefaction, peeling, etc.)?
Was there a difference in application after having a
How did it influence your ability to
perform power drills?
How did il inlluence your ability to
perform jogging?
How did il intluence your ability to dress?
How did it induence your ability to concentrate in
How did it influence your ability to eat?
How did it influence the ability to move your
How did it influetice the ability to move your
How did it influence the ability to move your neck?
Did it influence any other tnovements of other body
How difficult was it to remove ihe lotion at the end
of the study?
How long did it take to remove the lotion?
Did you feel it was possible to remove the lotion?
The results of the questionnaire filled in at the end of the study are presented
as the mean score for each question.
Mitny highly loxic CWAs exert their effect through the dermal
exposure route, either by vapors or droplets.'"'^''* Consensus
protective measures include mainly physical protection with
specialized outfits. Yet, integration areas, such as neck, armpits,
groin, waist, wrists, and ankles are a weak link for penetration
and exposure to CWAs. Previous preclinical studies indicated
that IBl lotion, a passive protective lotion against CWAs, sig-
nificantly reduced the toxicity of sulfur mustard and VX.''
The IBl lotion contains ingredients approved for human use
and has successfully passed the safety testing on animals and
humans."" A major concern regarding future use of the topical
skin protectant was the possibility, although faint, that danger-
ous amounts of magnesium might accumulate in plasma when
applying the lotion repeatedly. Thus, the main goals of the cur-
rent study were to test the dermatological and systemic safety
of this product in repeated applications and especially to rule
out ihe possibility of reaching dangerous levels of plasma Mg.
Magnesium is the fourth most common cation in the
body and the third most common intracellular cation (mainly
in muscle and liver).'^'"' The normal plasma concentra-
tion ranges between 1.5 and 2.3 mg/dL (1.2-1.9 mEq/L;
0.62-0.94 mmol/L), with some variation between clinical
laboratories. Only 1-2% of body magnesium is extra-
cellular (60% ionized; 15% complexed; 25% protein bound).
Magnesium is a necessary cofactor for hundreds of enzymes.
It is important for membrane stabilization and nerve conduc-
tion.''^ Renal excretion is tbe principal regulator of magne-
sium balance. Clinically significant hypermagnesemia. albeit
unusual, is almost always secondary to excessive intake. Tbe
kidneys' ability to excrete excessive magnesium is dimin-
ished in patients with chronic renal failure. Massive paren-
teral infusions of magnesium salts, which overwhelm renal
excretory mechanisms, have been reported with inadvertent
intravenous infusion, urologie procedures involving irriga-
tion with magnesium salts, and ingestion of large quantities of
magnesium-containing antacids and cathartics."' To tbe best
of our knowledge, there is no published scientific evidence
on transdermal absorption of magnesium. The symptoms of
bypermagnesemia correlate roughly with serum concentra-
tions but depend on the rate of increase and host factors.'^
January 2009
Phase I Study of a
Skin Protectant Against Chemical
TABLE III. Magnesiutn Levels of the Placebo atid Drug Groups
Sample A Placebo Mean Mg Leve! (mg/dL) n = 13
1 (Baseüne) 2.06(±0.ll)
2 2.33 (±0-17)
3 2.!6(±O.12)
4 2.25 (±0.15)
Samp!e B Placebo Mean difference from baseline tmg/dLj n = 13
2 0.27 (±0.14)
3 O.!O(±O.l)
4 0.19 (±0.16)
IBI Mean Mg Levels (mg/dL%)rt =
2.08 (±0.08) 0.8
2.26(±0.16) 0.24
2.18 (±0.20) 0.75
2.I8(±O.19) 0.16
I. Mean difference from baseline (mg/dL) n
2[ /)-Value
O.I8(±O.18) 0.15
0.10 (±0.21) 0.94
0.10 (±0.23) 0.20
(A) Results show the mean Mg va!ues of each group in al! individual time points, as indicated. (B) Differences between magnesium concentrations in the two
groups, relative to baseline values.
Usually, symptoms do not appear when plasma magnesium
levels are <4.5 mg/dL.'"^ Hypermagnesemia impairs neuromus-
cular junction transmission by decreasing ucetylcholine release
from the presynaptic membrane, thus producing hypotonia,
hyporeflexia. and weakness.''^ Paralysis occurs at high concen-
trations. Direct central nervous system depression causes leth-
argy and sleepiness. It is also associated with hypotension and
flushing owing to vascular dilation. Hypotension can be pro-
found at plasma levels of 4-5 mEq/L because of
direct effect
on cardiac function. At the same levels hypermagnesemia
typically results in loss of deep tendon reflexes. At levels >5
[TiEq/L central nervous system depression may range from
drowsiness to coma. Electrocardiogram changes occur at lev-
els of 5-10 mEq/L. including prolonged P-R. QRS. and Q-T
intervals. Serum levels of 9-12 mEq/L may cause apnea and
cardiovascular collapse.'' Severe hypermagnesemia includes
nausea, vomiting, hypocalcaemia. and can cause parasym-
pathetic blockade, fixed dilated pupils, and neuromuscular
blockade mimicking a midbrain syndrome.'^
We found no significant rise in blood Mg levels during
repetitive applications. Allegedly, a significant rise could be
observed between the first test obtained a week before the
study and the other tests obtained during the study. However,
this difference was very small and within the normal Mg range
(no clinical relevance) and may be attributed to the different
hour in which the samples were obtained. Indeed, baseline
samples were obtained at IO:3Oam-l
and the other tests
at 12:30pm-l:30pm. Two sampîes in which a higher than nor-
mal level of Mg was recorded in two volunteers applying the
IBl lotion might be explained by the normal diurnal change
in blood Mg levels, although blood samples were drawn at the
same time every day tluring the application study. Our main
concern was from tnuch higher blood Mg levels that might
cause dangerous symptoms, even if only transiently elevated.
Itnportantly. these slightly above normal values were far from
being considered dangerous, especially in young healthy indi-
viduals with normal renal functions. Although there is a possi-
bility that a larger sample size will uncover a group of subjects
with a significant rise in blood Mg levels, we tbink that the
existing evidence supported by animal studies"* is sufficient to
conclude that the use of IB
lotion does not lead to increased
serum Mg levels and is safe to use from this perspective.
Members of the review board of the Israeli Defense
Force's Medical Corps raised concerns of a potential effect
of IBl application on liver functions, as well as on complete
blood count, because of an inflammatory response, although
there was no evidence of any such changes in animal stud-
Hence, complete blood counts and liver function tests
were taken as part of the screening procedures and to rule out
clues for inflatntTiation that might follow dermal application
of the lotion. There was no evidence of any such changes in
the animal studies, and as estimated, there were also no sig-
nificant changes in the complete blood count and liver func-
tion measurements in either group in our study, except for a
very mild increase in white blood count ob.served post study
in both groups. However, as the difference was very small
and absolute values were within the normal range, it was
probably unrelated to the chemical composition of the IBl
and might reflect a mild stress, perhaps because of repeated
drawing of blood. No significant values could be observed
in the volunteers who complained of a transient burning
sensation (data not shown). Renal function tests were obtained
to make sure the basic status of the volunteers was normal and
was not altered during the study. No significant changes were
recorded in renal function tests, in either group. We conclude
that repetitive application of IBl does not cause measurable
inflammatory changes or renal or liver abnormalities.
Before this study, irritation and sensitivity tests were per-
formed in a well-recognized medical institute in the country,
which showed neither irritation nor sensitivity among 50 par-
ticipants.^ Here, however, several volunteers reported a short-
lasting burning sensation when applying the lotion on freshly
shaved skin, yet there were no persistent signs of irritation as
deñned by a dermatologist. The volunteers noted that it was
present for only a short period of time and resembled the feel-
ing of applying an aftershave. No difference could be identified
between the placebo and the IB
groups. As was mentioned
earlier, no changes were found in the complete blood count of
these volunteers, as might appear in an inflammatory reaction.
The second goal of the study was to find out whether the
topical skin protectant interferes with routine daily tasks. The
volunteers' impression was that repetitive applications do
not interfere with various daily activities, including writing,
jogging, and other sports activities, as detailed in Table IL
Jatiuary 200951
Phase I Study of a Topical Skin Protectant Against Chemical
We have no explanation for the difference concerning the
wearing of clothing and performing power drills, especially as
there was no difference in the consistency of
lotion and
the placebo. These differences may not reflect any practical
difficulties or differences. Alternatively, the study eventually
included a limited number of subjects. To attain confidently
significant results a larger group of volunteers is needed.
The limited number of volunteers in our study is one of
its major limitations. Though the final number of volunteers
participating in the study was statistically sufficient, it was
advisable to have a larger sample size. Unfortunately, >80%
of potential volunteers on the base did not want to take part
in this study, most of them because of the requirement of
drawing several blood samples during the study.
With the combination of previous animal studies, irritation and
sensitivity tests, and results that show safety and convenience,
we believe that the IBI lotion should be considered as a safe
adjunct to other CBRN protective measures of field soldiers.
We thank Dr. Tamar Kadar and the teams of the Pharmacology and Organic
Chemistry Departments at the Israel Institute for Biological Research, for
their invaluable help in performing this study.
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52MILITARY MEDICINE, Vol. 174, January 2009
... We have developed a topical skin protectant that is applied onto the skin before exposure and prevents the penetration of warfare agents such as SM and VX through the skin and thus confers a highly efficient protection against the hazard they pose [2]. The formulation coded IB1 is a hydrophilic water-based solution comprised of magnesium sulfate and glycerin and it was shown to be safe in preclinical and phase I studies [3]. IB1 was registered and approved by the Israel Ministry of Health as Dermostyx protective solution and is commercially available (Rekah Pharm, Israel). ...
... The longest pretreatment duration that was tested for the efficacy of SERPACWA, the TSP used by the US military, was 5 h [23,24]. IB1 is absorbed into the stratum corneum of the skin and remains there and we have shown that the ingredients are not absorbed into the circulation [3]. The protective mechanism of this preparation seemed to be primarily due to alterations in the physico-chemical properties of the stratum corneum that turned hydrophilic by the glycerin. ...
... When using glycerin, the hydration effect was long-lasting and the lipophilic stratum corneum turned hydrophilic as demonstrated by the histochemical staining of phospholipids. Another advantage of glycerin is that it does not penetrate from the stratum corneum into the circulation as shown in preclinical [2] and Phase I clinical [3] studies. The addition of magnesium sulfate into the glycerin solution decreased the solubility of the toxic agents in the stratum corneum water phase, a process known as " salting out " . ...
... IB1 (Dermostyx), a topical skin lotion protectant resistant to chemical agents, was developed at the Israel Institute for Biological Research (IIBR). It was successfully tested in a pig model, showing a significant reduction of sulfur mustard and VX toxicity, and has also passed successfully Phase I safety testing [24,25]. ...
... IB1 is effective immediately upon application and remains efficient for hours (tested up to 12 hours) in reducing the toxicity of sulfur mustard and VX in dermal exposure [25]. IB1 has successfully passed the safety testing in both animals and humans [24,25], and is approved by the Israel Ministry of Health and in Europe for skin application on up to 25% of body surface area, currently aimed for C-PPE integration areas or for relatively susceptible skin areas (Neck, armpits, and groin). ...
We aimed to evaluate the performance of medical personnel in using the IB1 topical protective lotion on their hands and wrists together with standard disposable medical gloves, compared to standard-issued medical chemical protective gloves. This randomized cross-over study included 144 medical personnel. Primary endpoints were time-to-completion of autoinjection; success rate, number of attempts, and time-to-achieve successful endotracheal intubation; time-to-achieve satisfactory tube fixation; time-to-draw and inject the content of an ampoule; and the total time-to-perform all medical procedures. Secondary endpoints included the subjective assessment of convenience to perform these four procedures with each protective measure. Mean time was significantly shorter using IB1 compared to chemical protective gloves for tube fixation, ampoule drawing, and the total time-to-perform all procedures (58.6±22.7 seconds vs. 71.7±29.7; 31.5±21.8 vs. 38.2±19.4; 137.4±56.1 vs. 162.5±63.6, respectively; P<.001 for all). For all medical procedures, the use of IB1 was reported as significantly more convenient than the use of chemical protective gloves (P<.001 for all comparisons). IB1 with standard medical gloves significantly shorten the time-to-perform medical procedures requiring fine motor dexterities and is subjectively more convenient than chemical protective gloves. IB1 should be considered as an appropriate alternative for medical teams in a chemical event.
... There were no significant differences in magnesium levels between the placebo and the study groups in any of the applications. No toxic levels of magnesium were found in either group [20]. ...
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In the following review, we evaluated the current literature and evidence-based data on transdermal magnesium application and show that the propagation of transdermal magnesium is scientifically unsupported. The importance of magnesium and the positive effects of magnesium supplementation are extensively documented in magnesium deficiency, e.g., cardiovascular disease and diabetes mellitus. The effectiveness of oral magnesium supplementation for the treatment of magnesium deficiency has been studied in detail. However, the proven and well-documented oral magnesium supplementation has become questioned in the recent years through intensive marketing for its transdermal application (e.g., magnesium-containing sprays, magnesium flakes, and magnesium salt baths). In both, specialist and lay press as well as on the internet, there are increasing numbers of articles claiming the effectiveness and superiority of transdermal magnesium over an oral application. It is claimed that the transdermal absorption of magnesium in comparison to oral application is more effective due to better absorption and fewer side effects as it bypasses the gastrointestinal tract.
Magnesium is an important element that has essential roles in the regulation of cell growth, division, and differentiation. Mounting evidence in the literature suggests an association between hypomagnesemia and all-cause mortality. In addition, epidemiologic studies have demonstrated that a diet poor in magnesium increases the risk of developing cancer, highlighting its importance in the field of hematology and oncology. In solid malignancies, hypomagnesemia at diagnosis portends a worse prognosis. However, little is known about prognosis in patients with hypomagnesemia and blood cancers in general; lymphoma more specifically. Hypomagnesemia has been associated with a higher viral load of the Epstein Barr virus, a virus associated with a multitude of hematologic malignancies. The role of magnesium in the immune system has been further elucidated in studies of patients with a rare primary immunodeficiency known as XMEN disease (X-linked immunodeficiency with Magnesium defect, Epstein-Barr virus (EBV) infection, and Neoplasia disease). These patients have a mutation in the MAGT1 gene, which codes for a magnesium transporter. The mutation leads to impaired T cell activation and an increased risk of developing hematologic malignancies. In this review we discuss the relevance of magnesium as an electrolyte, current measurement techniques, and the known data related to cause and prognosis of blood cancers. The goal is to use these data to stimulate additional high-quality and well powered studies to further investigate the role of magnesium in preventing cancer and improving outcomes of patients with malignancy and concomitant magnesium deficiency.
1. Sulphonation is unusual amongst the common Phase II (condensation; synthetic) reactions experienced by xenobiotics, in that the availability of the conjugating agent, sulphate, may become a rate-limiting factor. This sulphate is derived within the body via the oxygenation of sulphur moieties liberated from numerous ingested compounds including the sulphur-containing amino acids. Preformed inorganic sulphate also makes a considerable contribution to this pool. 2. There has been a divergence of opinion as to whether or not inorganic sulphate may be readily absorbed from the gastrointestinal tract and this controversy still continues in some quarters. Even more so, is the vexing question of potential absorption of inorganic sulphate via the lungs and through the skin. 3. This review examines the relevant diverse literature and concludes that sulphate ions may move across biological membranes by means of specific transporters and, although the gastrointestinal tract is by far the major portal of entry, some absorption across the lungs and the skin may take place under appropriate circumstances.
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The nerve agents, GA, GB, and VX are organophosphorus esters that form a major portion of the total agent volume contained in the U.S. stockpile of unitary chemical munitions. Congress has mandated the destruction of these agents, which is currently slated for completion in 2004. The acute, chronic, and delayed toxicity of these agents is reviewed in this analysis. The largely negative results from studies of genotoxicity, carcinogenicity, developmental, and reproductive toxicity are also presented. Nerve agents show few or delayed effects. At supralethal doses, GB can cause delayed neuropathy in antidote-protected chickens, but there is no evidence that it causes this syndrome in humans at any dose. Agent VX shows no potential for inducing delayed neuropathy in any species. In view of their lack of genotoxcity, the nerve agents are not likely to be carcinogens. The overreaching concern with regard to nerve agent exposure is the extraordinarily high acute toxicity of these substances. Furthermore, acute effects of moderate exposure such as nausea, diarrhea, inability to perform simple mental tasks, and respiratory effects may render the public unable to respond adequately to emergency instructions in the unlikely event of agent releaase, making early warning and exposure avoidance important. Likewise, exposure or self-contamination of first responders and medical personnel must be avoided. Control limits for exposure via surface contact of drinking water are needed, as are detection methods for low levels in water or foodstuffs. Images Figure 2.
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With the invention of the ion-selective electrode (ISE), ionic magnesium (iMg) is a common blood assay. This could be advantageous, as iMg is the biologically active form of Mg. There is some evidence that iMg has considerable within subject variability. Individual ranges averaged.08 mmol/L (range.05 to.14). Coefficients of variation (CV) ranged from 3% to 7% (mean 4%) while analytical variation was determined to be 2.3%. Biological variability thus accounts for almost half of the variability, which is clinically significant, as 9 of the 13 subjects recorded at least one value below a reference range of.46 -.60 mmol/L. A significant within-day variation (p <.001) was noted, with differences between 7:00 and 10:00 as well as 10:00 and 22:00. Between day variations were not significant (p =.56). A plausible explanation of this data is that iMg has a circadian rhythm. Thus, cautious interpretation of single iMg values is warranted until future research determines the nature of iMg variability.
25 subjects volunteered to document circadian changes in serum magnesium. 4 groups were formed: 7 healthy young males (24.0 years +/- 3.9), 6 elderly males (82.5 years +/- 7.5), 6 elderly females 81.2 years +/- 10.7) and 6 elderly insame subjects of both sexes (80.5 years +/- 8.6). They were socially synchronized with a diurnal activity (07.00 to 21.00 for the old subjects; 07.00 to 23.00 for the young ones) and nocturnal rest. The subjects followed a spontaneous diet. Venous blood was sampled at 4-h intervals and fixed clock hours (07.45, 11.45, 15.45, 19.45, 23.45, 03.45) during 24 h. The single cosinor method was used for the statistical analysis of the time series. A statistically significant circadian rhythm is detected in three of the groups: young males, elderly males and elderly females (no rhythm detection in elderly insane subjects). The 24-h mean is higher in elderly subjects than in the young one. The rhythm amplitude is larger in elderly males than in young ones. The acrophase (peak time) location in the 24-h scale is 10.12 h for elderly females, 11.35 h for elderly males and 16.36 h for young males.
The use of a topical skin protectant (TSP) as a means of protecting troops from percutaneous chemical warfare agent (CWA) exposure has been proposed since these weapons were first used during World War I. The TSP is applied to vulnerable skin surfaces prior to entry into a chemical combat area. In 1990, the US Army Medical Research Institute of Chemical Defense transferred two non-reactive TSPs into advanced development. Following US Food and Drug Administration approval, the final product is expected to be available to soldiers in 1999. A continuing research effort is designed to develop a second-generation TSP that will increase effectiveness and also decontaminate CWAs into non-toxic products. We identified a list of 29 reactive moieties as potential additives to the TSP formulation. All candidate formulations are evaluated in a decision tree network, consisting of a series of 11 efficacy testing models. A prototype formulation (ICD 2701) containing the reactive ingredient S-330 has dramatically improved the protection against saturated sulfur mustard vapor. In addition, we have discovered a compound (ICD 2837) that significantly increases the skin's natural resistance to CWA penetration. Our goal is to transfer a significantly improved TSP formulation into advanced development by 1999.
The mouse ear vesicant model (MEVM) provides a quantitative edema response as well as histopathological and biochemical endpoints as measurements of inflammation and tissue damage following exposure to the chemical warfare agent sulfur mustard (HD). In the MEVM, several topically applied anti-inflammatory agents provided a significant degree of protection against HD-induced edema and dermal-epidermal separation. This study evaluated the protective effects of three of these pharmacological compounds when administered systemically in the MEVM. Alzet osmotic pumps were used to deliver a subcutaneous dose of the appropriate anti-inflammatory agent, starting 24 h before exposure to sulfur mustard and continuing until 24 h post-exposure to HD. Twenty-four hours after pump implantation, 5 microl of a 195 mM (0.16 mg) solution of sulfur mustard (density = 1.27 g ml(-1); MW = 159; purity = 97.5%) in methylene chloride was applied to the inner surface of the right ear of each mouse. Sulfur mustard injury in the mouse ear was measured by both edema response (fluid accumulation) and histopathological damage (necrosis, epidermal-dermal separation). The systemic administration of hydrocortisone, indomethacin and olvanil provided a significant reduction in edema (24%, 26% and 22%, respectively) from the positive control. Compared to HD-positive controls, hydrocortisone, indomethacin and olvanil caused a significant reduction in subepidermal blisters (71%, 52% and 57%, respectively) whereas only hydrocortisone produced a significant reduction in contralateral epidermal necrosis (41%). We show here that these anti-inflammatory drugs are effective when administered systemically in the MEVM.
In spite of several decades of research, no effective treatment to skin injuries following exposure to sulfur mustard (HD) has yet been found. In the present study, the mouse ear vesicant model was applied to awake mice in order to evaluate the efficiency of potential anti-inflammatory treatments in preventing HD-induced skin damages. Clinical follow-up and histological evaluation were used to characterize the injuries to the skin and to evaluate the efficiency of the drugs that were applied. Thus, the extent of mouse ear oedema and the histopathological changes following a single application of 0.2 or 1 microL of neat HD for 10 min (representing moderate and severe lesions, respectively), were monitored. Typical HD skin lesions were observed including epithelial and dermal damage. The development of the injury in mouse ears was found to be very similar to that reported in human skin. Screening of post-exposure topical steroids and non-steroidal antiinflammatory drugs (NSAIDs) proved that HD-induced inflammation could be diminished significantly as long as the treatment was applied during the early stages following exposure. A combined application of these drugs approved to be particularly effective in reducing inflammation.
Sulfur mustard and VX are potent chemical warfare agents that penetrate rapidly through the skin, causing severe prolonged injuries and sometimes death. To develop a topically applied pretreatment that will act as a barrier and prevent the absorption of these agents through the skin, reducing morbidity and saving life. Several formulations were developed and tested in preclinical animal studies in pigs. The protecting cream was applied as a single application (0.5-1 ml/100 cm2) prior to exposure (10 minutes to 12 hours) to sulfur mustard or VX. Assessment of sulfur mustard-induced skin damage was based on clinical and histologic evaluations. When tested against VX, clinical signs and blood cholinesterase activity were monitored. At the final stage of development, safety studies were conducted in animals and in human volunteers. The formulation that gave the best results, coded IB1 (under patent application), provided significant protection against a 1 hour exposure to sulfur mustard (droplets or vapor). All the pigs pretreated with IB1 cream survived a 1-4 hour challenge of 2xLD50 VX and did not exhibit any overt clinical signs. Protection was exhibited even when the cream was applied 12 hours (single application) prior to exposure. IB1 was found to be non-irritating in animals and humans. No adverse effects were found in a Phase I clinical study in young healthy volunteers when the cream was applied to around 20% of the skin surface (results presented elsewhere). IB1 cream has been shown to be a safe and effective topical skin protectant against the chemical warfare agents sulfur mustard and VX.
Clinical considerations in mustard poisoning
  • F R Sidell
  • C G Hurst
Sidell FR. Hurst CG: Clinical considerations in mustard poisoning. In: Chemical Warfare Agents, p 51. Edited by Somani SM: New York, Academic Press, 1992.
Emergency response to a chemical warfare agent incident: domestic preparedness, first response, and public health considerations
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  • S M Alexander
Moore DH. Alexander SM; Emergency response to a chemical warfare agent incident: domestic preparedness, first response, and public health considerations. In: Chemical Warfare Agents: Toxicity at Low Levels, pp 409-435. Edited by Somani SM, Romano JA;