Phase I Study of a Topical Skin Protectant Against Chemical Warfare AgentsINTRODUCTION
Sulfur mustard is a potent vesicant vesicant /ves·i·cant/ (ves´i-kant)
1. producing blisters.
2. an agent that so acts.
n. that penetrates the human skin easily and although blisters appear within hours after exposure, the molecular damage occurs within minutes.1-5 Despite continuing efforts there are still no antidotes available.1-3,5-8 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).1,9 Current chemical, biological, and radio-nuclear (CBRN CBRN Chemical, Biological, Radiological, and Nuclear
CBRN Caribbean Basin Radar Network ) personal protection equipment includes a mask, protective clothing, gloves, and overboots. Any penetration of the above mentioned CWAs through gaps in the protective equipment entails a potential life-threatening risk.
A topically applied pretreatment pretreatment,
n the protocols required before beginning therapy, usually of a diagnostic nature; before treatment.
n See predetermination. may act as a dermal dermal /der·mal/ (der´mal) pertaining to the dermis or to the skin.
der·mal or der·mic
Of or relating to the skin or dermis. barrier, preventing the absorption of these agents through the skin and thus their respective toxicity.10 Such skin protectant protectant /pro·tec·tant/ (pro-tek´tant) protective.
1. affording defense or immunity.
2. an agent affording defense against harmful influence. may serve as an additional means of protection A means of protection is some contract or guarantee of security for body or property. It is usually achieved, in a modern state society, by agreeing to some social contract including a monopoly on violence, e.g. in conjunction with other physical protection components. Towards this end, the primary application areas should include the integration areas of the personal protective equipment, i.e., the neck, armpits, groin, waist, wrists, and ankles, which are also considered to be relatively sensitive skin areas.1,2,5 The "topical skin protectant" strategy has been adopted by several countries so far, including Israel.10
IBI See Information Builders. , a topical skin protectant resistant to CWAs that was developed at the Israel Institute for Biological Research Israel Institute for Biological Research (IIBR) is a government defense research institute specializing in biology, medicinal chemistry and environmental science. It is located in Ness Ziona, 20 kilometers south of Tel Aviv. (IIBR IIBR Israel Institute for Biological Research ), was successfully tested in various animal models.4 Using the well-established primary skin irritation skin irritation,
n reaction to a particular irritant that results in inflammation of the skin and itchiness. Draize test,11 the protectant was demonstrated to be nonirritating in guinea pigs and in rabbits. No adverse dermatological or systemic effects were found in a long-term toxicological study in pigs following an overdose application of the protectant (covering >20% of the skin surface, applied three times per day for 2 weeks). Evaluation included a clinical follow-up for 1 month, blood and urine biochemistry, including magnesium (Mg) levels, and pathology. No detectable levels of the protectant ingrethents were found in blood and urine during the entire monitoring period.4 Also, blood and urine Mg levels were not increased. Irritation and sensitivity tests were performed on 50 human volunteers (11 males, 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 sensitization sensitization /sen·si·ti·za·tion/ (sen?si-ti-za´shun)
1. administration of an antigen to induce a primary immune response.
2. exposure to allergen that results in the development of hypersensitivity. .4
Here we tested the medical safety of repeated topical application of the IB1 lotion in a randomized ran·dom·ize
tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es
To make random in arrangement, especially in order to control the variables in an experiment. placebocontrolled double-blind phase I clinical study in young healdiy volunteers. Since the lotion includes a relatively high content of magnesium sulfate magnesium sulfate
A colorless crystalline compound used as a cathartic and applied locally as an anti-inflammatory agent.
magnesium sulfate Warning - High-alert drug! , potential changes in serum Mg levels were monitored, as well as other hematological hematological, hematologic
pertaining to or emanating from blood cells.
total and differential white cell counts, hematocrit estimation, erythrocyte count. and biochemical parameters, local dermatological adverse effects, and convenience of use.
MATERIALS AND METHODS
The study was approved by the review board of the Israeli Defense Force's (IDF (Intermediate Distribution Frame) A wiring rack located between the MDF (main distribution frame) and the intended end user devices (telephones, routers, PCs, etc.). Cables run from the outside world to the MDF and then to the IDFs. See MDF and wiring rack. ) Medical Corps and was conducted according to the Declaration of Helsinki For the political accords, see .
. There is also another Declaration of Helsinki, dealing with the Information Society. Introduction
The Declaration of Helsinki, was developed by the World Medical Association . All volunteers gave their written informed consent.
Preliminary Application Test
To determine the amount of IBl lotion needed for each application, an application test was performed before the main study. In this preliminary study 10 volunteers received small glass vials containing 20 ml of the IBl and were asked to cover relevant areas as described in Figure 1. The application 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 Liver Function Tests Definition
Liver function tests, or LFTs, include tests for bilirubin, a breakdown product of hemoglobin, and ammonia, a protein byproduct that is normally converted into urea by the liver before being excreted by the kidneys. , and renal function tests to participate. Soldiers with any chronic or acute disease (especially dermatological diseases) or receiving any medical treatment were excluded. This excluded soldiers with asthma, atopic dermatitis Atopic Dermatitis Definition
Eczema is a general term used to describe a variety of conditions that cause an itchy, inflamed skin rash. Atopic dermatitis, a form of eczema, is a non-contagious disorder characterized by chronically inflamed skin and , previously known allergy, allergic rhinitis, allergic conjunctivitis, sun bums, skin lesions at the application areas, and soldiers that for any reason could not replace contact lenses with eyeglasses eyeglasses or spectacles, instrument or device for aiding and correcting defective sight. Eyeglasses usually consist of a pair of lenses mounted in a frame to hold them in position before the eyes. . Every volunteer had the right to stop participation at any time during the study. In addition, each volunteer filled and signed an informed consent form and a medical questionnaire.
The study was designed as a randomized placebo-controlled double-blind study. The IBl and the placebo lotions were prepared at the HBR HBR Harvard Business Review
HBR High Bit Rate
HBR Human Behavioral Representation
HBR Heijmans Blackwell Remediation
HBR Hydrobromide Acid
HBR House Budget Resolution
HBR Hybrid Block Repair
HBR Host-Based Replication and were coded by medical personnel at the IDF's Medical Corps, who were not involved in any other part of the experiment, including design, performance, or analysis. Codes were locked throughout the experiment. The researchers, who enrolled the volunteers, drew the blood, took vital signs, 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 all analyses were completed. Coding was revealed only at the end of the study by the same personnel that coded them before the study.
The placebo was the vehicle of the IB 1 lotion, consisting of 87% glycerin glycerin /glyc·er·in/ (-in) a clear, colorless, syrupy liquid used as a laxative, an osmotic diuretic to reduce intraocular pressure, a demulcent in cough preparations, and a humectant and solvent for drugs. Cf. glycerol. (Merck, Israel) and 13% Aqua without any magnesium. Both placebo and IBl lotions were indistinguishably 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 volunteers during the preparation day of the study (see below "Experimental Protocol"). Each volunteer was assigned one vial per application.
A preparation day preceded the actual study by 1 week. Study protocol included 4 consecutive days in which a total of nine applications were carried 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 (baseline Mg levels, complete blood count, renal functions, and liver functions). The dosing schedule was defined on the basis of the pre-clinical experiments.4 The lotion was applied on six body areas: the neck, axillae Axilla (plural, axillae)
The medical term for the armpit.
Mentioned in: Hyperhidrosis , 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 drawings. 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 noting, the vials were collected by the researchers after each application.
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 IBl lotion contains magnesium sulfate, renal function tests were taken as baseline and at the end of the study, and blood Mg levels were monitored daily to verify that repetitive IBl application does not lead to a dangerous increase. Because of the diurnal diurnal /di·ur·nal/ (di-er´nal) pertaining to or occurring during the daytime, or period of light.
1. Having a 24-hour period or cycle; daily.
2. changes in Mg levels,12,13 blood samples were drawn at the same time every day between 12:30pm and 1 :30pm, except for the baseline tests, which were obtained between 10:30am and 11:00am. Baseline 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. Blood samples were transferred immediately in a chilled receptacle to a medical laboratory 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 activity, including physical trainings, or on any clothing, including uniforms, were placed on the volunteers. 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 allergic contact dermatitis Allergic dermatitis Dermatology A condition caused by cell-mediated immunity due to contact with haptens–eg, nickel, chromates, ursodiols in poison ivy and poison oak, synthetic chemicals, drugs, cosmetics, jewelry, neomycin 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 second questionnaire on the influence of the lotion on daily activities and their comments about the product (data not shown).
The minimal number of subjects for the study was decided on the basis of the following considerations: significance level (a) 0.05; statistical power (l-ß) 0.8; anticipated effect size (f^sup 2^) 0.4. The minimal number accordingly was calculated to be 22 (1 1 in each group); however, since several dropouts were expected, die study was started with 51 subjects (of which 17 indeed dropped out).
Statistical analyses were performed using SAS (1) (SAS Institute Inc., Cary, NC, www.sas.com) A software company that specializes in data warehousing and decision support software based on the SAS System. Founded in 1976, SAS is one of the world's largest privately held software companies. See SAS System. for Windows version 9.1 (SAS Institute, Ine, Cary, NC). Normality of variables distribution was tested with the Smirnov-Klimigorov test. Plasma Mg levels of the two groups (IB 1 lotion and placebo) were compared for each day of lotion application with die Mann-Whitney nonparametric test. In addition, differences between Mg levels at each stage and the baseline levels 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 asthma, 2 other volunteers were diagnosed with mild anemia at me baseline complete blood count (10.2 mg/dL and 10.6 mg/ dL), 1 volunteer had a high bilirubin Bilirubin
The predominant orange pigment of bile. It is the major metabolic breakdown product of heme, the prosthetic group of hemoglobin in red blood cells, and other chromoproteins such as myoglobin, cytochrome, and catalase. 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 tonsillitis
Inflammatory infection of the tonsils, usually with hemolytic streptococci (see streptococcus) or viruses. The symptoms are sore throat, trouble in swallowing, fever, and enlarged lymph nodes on the neck. with fever that appeared on the second and third days of the study, and an additional 9 volunteers dropped out of the study at various stages because of nonmedical 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 mat 21 volunteers received the IBl and 13 received placebos: 26 males (17 in the IBl group, 9 in the placebo group) and 8 females (4 in each application group). The effect of gender on the results could not be measured because of small sample size.
No serious adverse effects were reported throughout the study. Forty percent of the male volunteers in the IB 1 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 (p-value = 0.04) and showed a strong trend in the IBl group (p- value = 0.06). There were no significant differences among renal and liver function tests between the baseline and the poststudy analyses (Table I).
After completion of the experimental protocol all volunteers 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 IBl group mainly (Table II). However, these interferences did not seem to impair the solthers' overall physical performance and hence may not have any practical implication. AU 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 concentrate during lectores (Table II).
Blood Mg levels were within the normal range in all sample points in both groups (1.53 mg/dL^2.6 mg/dL), except for two sporadic samples from two different volunteers in the IBl group (2.9 mg/dL in the third sample in one volunteer 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 IBl group in any of the tested time points (Table ??). 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 baseline levels were calculated 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 1 were significantly lower than other measurements in the same group in both placebo and IBl groups (p-value < 0.001 and/p-value < 0.01, respectively). However, these differences were very small and within the normal Mg range.
Many highly toxic CWAs exert their effect through the dermal exposure route, either by vapors or droplets.1-3,5,14 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 G?1 lotion, a passive protective lotion against CWAs, significantly reduced the toxicity of sulfur mustard and VX.4 The IBl lotion contains ingrethents approved for human use and has successfully passed the safety testing on animals and humans.4 A major concern regarding future use of the topical skin protectant was the possibility, although faint, that dangerous amounts of magnesium might accumulate in plasma when applying the lotion repeatedly. Thus, the main goals of the current study were to test the dermatologica! and systemic safety of this product in repeated applications and especially to rule out the possibility of reaching dangerous levels of plasma Mg.
Magnesium is the fourth most common cation cation (kăt'ī`ən), atom or group of atoms carrying a positive charge. The charge results because there are more protons than electrons in the cation. in the body and the third most common intracellular cation (mainly in muscle and liver).1516 The normal plasma concentration 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 extracellular (60% ionized i·on·ize
tr. & intr.v. i·on·ized, i·on·iz·ing, i·on·iz·es
To convert or be converted totally or partially into ions.
i ; 15% complexed; 25% protein bound). Magnesium is a necessary cofactor cofactor
An atom, organic molecule, or molecular group that is necessary for the catalytic activity (see catalysis) of many enzymes. A cofactor may be tightly bound to the protein portion of an enzyme and thus be an integral part of its functional structure, or it may for hundreds of enzymes. It is important for membrane stabilization and nerve conduction.15 Renal excretion is the principal regulator of magnesium balance. Clinically significant hypermagnesemia, albeit unusual, is almost always secondary to excessive intake. The kidneys' ability to excrete excrete /ex·crete/ (eks-kret´) to throw off or eliminate by a normal discharge, such as waste matter.
To eliminate waste material from the body. excessive magnesium is diminished in patients with chronic renal failure chronic renal failure Chronic kidney failure Nephrology A slow decline in renal function, which may be 2º to chronic HTN, DM, CHF, SLE, or sickle cell anemia and, if extreme, leads to ESRD, mandating kidney dialysis; an abrupt decline in renal function may be . Massive parenteral parenteral /pa·ren·ter·al/ (pah-ren´ter-al) not through the alimentary canal, but rather by injection through some other route, as subcutaneous, intramuscular, etc.
1. infusions of magnesium salts, which overwhelm renal excretory ex·cre·to·ry
Of, relating to, or used in excretion.
pertaining to excretion.
see elimination behavior. mechanisms, have been reported with inadvertent intravenous infusion, urologie procedures involving irrigation irrigation, in agriculture, artificial watering of the land. Although used chiefly in regions with annual rainfall of less than 20 in. (51 cm), it is also used in wetter areas to grow certain crops, e.g., rice. with magnesium salts, and ingestion ingestion /in·ges·tion/ (-chun) the taking of food, drugs, etc., into the body by mouth.
1. The act of taking food and drink into the body by the mouth.
2. of large quantities of magnesium-containing antacids Antacids Definition
Antacids are medicines that neutralize stomach acid.
Antacids are used to relieve acid indigestion, upset stomach, sour stomach, and heartburn. and cathartics.16 To the best of our knowledge, there is no published scientific evidence on transdermal absorption of magnesium. The symptoms of hypermagnesemia correlate roughly with serum concentrations but depend on the rate of increase and host factors.16
Usually, symptoms do not appear when plasma magnesium levels are <4.5 mg/dL.15 Hypermagnesemia impairs neuromuscular junction transmission by decreasing acetylcholine acetylcholine (əsēt'əlkō`lēn), a small organic molecule liberated at nerve endings as a neurotransmitter. It is particularly important in the stimulation of muscle tissue. release from the presynaptic membrane, mus producing hypotonia hypotonia /hy·po·to·nia/ (-ton´e-ah) diminished tone of the skeletal muscles.
1. Reduced tension or pressure, as of the intraocular fluid in the eyeball.
2. , hyporeflexia, and weakness.15 Paralysis occurs at high concentrations. Direct central nervous system depression causes letiiargy and sleepiness. It is also associated with hypotension hypotension
or low blood pressure
Condition in which blood pressure is abnormally low. It may result from reduced blood volume (e.g., from heavy bleeding or plasma loss after severe burns) or increased blood-vessel capacity (e.g., in syncope). and flushing owing to vascular dilation dilation /di·la·tion/ (di-la´shun)
1. the act of dilating or stretching.
1. . Hypotension can be profound at plasma levels of 4-5 mEq/L because of a direct effect on cardiac function. At die same levels hypermagnesemia typically results in loss of deep tendon reflexes. At levels >5 mEq/L central nervous system depression may range from drowsiness to coma. Electrocardiogram electrocardiogram /elec·tro·car·dio·gram/ (-kahr´de-o-gram?) a graphic tracing of the variations in electrical potential caused by the excitation of the heart muscle and detected at the body surface. changes occur at levels of 5-10 mEq/L, including prolonged P-R, QRS QRS
A pattern seen in an electrocardiogram that indicates the pulses in a heart beat and their duration. Variations from a normal QRS pattern indicate heart disease.
Mentioned in: Bundle Branch Block , and Q-T intervals. Serum levels of 9-12 mEq/L may cause apnea and cardiovascular collapse.15 Severe hypermagnesemia includes nausea, vomiting, hypocalcaemia Noun 1. hypocalcaemia - abnormally low level of calcium in the blood; associated with hypoparathyroidism or kidney malfunction or vitamin D deficiency
hypocalcemia , and can cause parasympathetic parasympathetic /para·sym·pa·thet·ic/ (-sim?pah-thet´ik) see under system.
Of, relating to, or affecting the parasympathetic nervous system. blockade, fixed dilated dilated
a state of dilatation.
see congestive cardiomyopathy.
dilated pupil syndrome
see feline dysautonomia (Key-Gaskell syndrome). pupils, and neuromuscular blockade mimicking a midbrain midbrain: see brain. syndrome.15
We found no significant rise in blood Mg levels during repetitive applications. Allegedly, a significant rise could be observed between die first test obtained a week before die study and die 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 die samples were obtained. Indeed, baseline samples were obtained at 1 0:30am- 1 1 :00am and me other tests at 12:30pm-l:30pm. Two samples in which a higher than normal level of Mg was recorded in two volunteers applying the IBl lotion might be explained by me normal diurnal change in blood Mg levels, although blood samples were drawn at die same time every day during the application study. Our main concern was from much higher blood Mg levels tìiat might cause dangerous symptoms, even if only transiently elevated. Importantly, these slightly above normal values were far from being considered dangerous, especially in young healdiy individuals with normal renal functions. Although there is a possibility that a larger sample size will uncover a group of subjects with a significant rise in blood Mg levels, we think mat the existing evidence supported by animal studies4 is sufficient to conclude that the use of IBl 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 mere was no evidence of any such changes in animal studies. Hence, complete blood counts and liver function tests were taken as part of the screening procedures and to rule out clues for inflammation that might follow dermal application of the lotion. There was no evidence of any such changes in the animal stuthes, and as estimated, there were also no significant changes in the complete blood count and liver function measurements in either group in our study, except for a very mild increase in white blood count observed post study in bom groups. However, as the difference was very small and absolute values were within the normal range, it was probably unrelated to me chemical composition of me 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 me volunteers was normal and was not altered during the study. No significant changes were recorded in renal function tests, in eitiier 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 performed in a well-recognized medical institute in the country, which showed neither irritation nor sensitivity among 50 participants.4 Here, however, several volunteers reported a shortlasting burning sensation when applying the lotion on freshly shaved skin, yet there were no persistent signs of irritation as defined by a dermatologist. The volunteers noted that it was present for only a short period of time and resembled the feeling of applying an aftershave aftershave
a scented lotion applied to a man's face after shaving
aftershave , aftershave lotion after n → Rasierwasser nt . No difference could be identified between the placebo and the IB 1 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 II. 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 the IB 1 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 confidendy 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 stuthes, irritation and sensitivity tests, and results that show safety and convenience, we believe that the IB1 lotion should be considered as a safe adjunct to other CBRN protective measures of field solthers.
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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