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Daan Noort - One of the best experts on this subject based on the ideXlab platform.
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standard operating procedure for immunuslotblot assay for analysis of dna Sulfur Mustard adducts in human blood and skin
Journal of Analytical Toxicology, 2004Co-Authors: G P Van Der Schans, H P Benschop, Roos H Marsgroenendijk, L P A De Jong, Daan NoortAbstract:A standard operating procedure has been developed for an immunoslotblot assay of Sulfur Mustard adducts to DNA in human blood and skin for use in a field laboratory. A minimum detectable level of exposure of human blood in vitro (> or = 50 nM) Sulfur Mustard is feasible with the assay. In the case of human skin, a 1 s exposure to saturated Sulfur Mustard vapor (830 mg/m(-3)) could still be detected.
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diagnosis and dosimetry of exposure to Sulfur Mustard development of a standard operating procedure for mass spectrometric analysis of haemoglobin adducts exploratory research on albumin and keratin adducts
Journal of Applied Toxicology, 2001Co-Authors: Daan Noort, A. Fidder, Albert G Hulst, Leo P A De Jong, H P BenschopAbstract:Experiments were carried out to develop a standard operating procedure for analysis of Sulfur Mustard adducts to the N-terminal valine in haemoglobin and to explore adduct formation with albumin and keratin. In the first approach, gas chromatography-negative chemical ionization/mass spectrometry (GC-NCI/MS) of the thiohydantoin sample subsequent to the modified Edman degradation was performed using a thermodesorption/cold trap (TCT) injection technique (detection limit for in vitro exposure of human blood to Sulfur Mustard: 30 nM). In the second approach, the crude thiohydantoin sample was purified by solid-phase extraction procedures. In the third approach, the procedure was shortened significantly by performing the Edman degradation for 2 h at 60°C. Upon exposure of human blood to various concentrations of [14C]Sulfur Mustard, ca. 20% was covalently bound to albumin. One of the tryptic fragments (T5 containing an alkylated cysteine (HETE-(A-L-V-L-I-A-F-A-Q-Y-L-Q-Q-C-P-F-E-D-H-V-K); MW 2536 Da) could be detected sensitively with liquid chromatography/tandem mass spectrometry analysis (detection limits: ≥15 pg absolute and 1 μM for in vitro exposure of human blood). Upon exposure of human callus (suspensions in 0.9% NaCl; 500 mg ml-1) to various concentrations of [14C]Sulfur Mustard we found 15-20% of the added radioactivity covalently bound to keratin. Upon incubation with base, 80% of the bound radioactivity was split off as [14C]thiodiglycol. This result opens the way for sensitive mass spectrometric detection of Sulfur Mustard exposure of skin by gas chromatography/mass spectrometry of (derivatized) thiodiglycol. Copyright © 2000 John Wiley & Sons, Ltd.
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monitoring of in vitro and in vivo exposure to Sulfur Mustard by gc ms determination of the n terminal valine adduct in hemoglobin after a modified edman degradation
Chemical Research in Toxicology, 1996Co-Authors: A. Fidder, Daan Noort, Ad L De Jong, Hendrik C Trap, Hendrik P. BenschopAbstract:We report that exposure to the chemical warfare agent Sulfur Mustard can be monitored by means of a modified Edman degradation involving selective release of the N-terminal valine adduct of hemoglobin with the agent. The degree of alkylation of the N-terminal valine in human hemoglobin is approximately 1−2% of the total alkylation induced in hemoglobin upon treatment of human blood with Sulfur Mustard. After modified Edman degradation, followed by derivatization with heptafluorobutyric anhydride, the obtained pentafluorophenyl thiohydantion derivative of the valine adduct could be analyzed at a ≥0.5 fmol level by means of GC/MS under negative ion chemical ionization conditions. Applying this procedure, in vitro exposure of human blood to ≥0.1 μM of Sulfur Mustard could be determined. In vivo exposure of guinea pigs could also be established at 48 h after intoxication intravenously with 0.5 mg/kg (0.06 LD50) of the agent.
Brian A Logue - One of the best experts on this subject based on the ideXlab platform.
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rapid analysis of Sulfur Mustard oxide in plasma using gas chromatography chemical ionization mass spectrometry for diagnosis of Sulfur Mustard exposure
Journal of Chromatography A, 2018Co-Authors: Erica Manandhar, Adam Pay, Livia A Veress, Brian A LogueAbstract:Abstract Sulfur Mustard (SM) is the most utilized chemical warfare agent in modern history and has caused more casualties than all other chemical weapons combined. SM still poses a threat to civilians globally because of existing stockpiles and ease of production. Exposure to SM causes irritation to the eyes and blistering of skin and respiratory tract. These clinical signs of exposure to SM can take 6–24 h to appear. Therefore, analyzing biomarkers of SM from biological specimens collected from suspected victims is necessary for diagnosis during this latent period. Here, we report a rapid, simple, and direct quantitative analytical method for an important and early SM biomarker, Sulfur Mustard oxide (SMO). The method includes addition of a stable isotope labeled internal standard, SMO extraction directly into dichloromethane (DCM), rapid drying and reconstitution of the extract, and direct analysis of SMO using gas chromatography-chemical ionization-mass spectrometry. The limit of detection of the method was 0.1 μM, with a linear range from 0.5 to 100 μM. Method selectivity, matrix effect, recovery, and short-term stability were also evaluated. Furthermore, the applicability of the method was tested by analyzing samples from inhalation exposure studies performed in swine. The method was able to detect SMO from 100% of the exposed swine (N = 9), with no interferences present in the plasma of the same swine prior to exposure. The method presented here is the first of its kind to allow for easy and rapid diagnosis of SM poisoning (sample analysis
H P Benschop - One of the best experts on this subject based on the ideXlab platform.
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intravenous toxicokinetics of Sulfur Mustard and its dna adducts in the hairless guinea pig and marmoset
Prophylaxis and Therapy against Chemical Agents. Final report of the HFM-04 TG-004 for the Period 1999 to 2005, 2009Co-Authors: J P Langenberg, W E T Spruit, Willem C Kuijpers, R H Mars, H P M Van Helden, G P Van Der Schans, H P BenschopAbstract:ln order to provide a quantitative basis for pretreatment and therapy of intoxications with Sulfur Mustard the toxicokinetics of this agent as well as its major DNA-adducts are being studied in male hairless guinea pigs for the intravenous, respiratory and percutaneous routes. A highly sensitive method for bioanalysis of the intact agent in blood and tissues was developed, involving gas chromatography with automated thermodesorption injection and mass-spectrometric detection. Deuterated Sulfur Mustard is used as the internal standard. The absolute detection limit is 700 fg for Sulfur Mustard, which corresponds with a detection limit in blood of ca. 5 pg/ml. DNA-adducts are measured via the previously developed immuno-slot-blot method, using antibodies directed against the adduct of Sulfur Mustard to guanine. The intravenous 96-h LD50 of Sulfur Mustard in the hairless guinea pig was determined and appeared to be 8.2 mg/kg. The intravenous toxicokinetics of this dose in the hairless guinea pig are characterized by a very rapid distribution phase and a very slow elimination phase. A rapid adduct formation occurs in blood and lung, and subsequently in other organs. The adduct levels in lung were remarkably high. A considerable repair of the adducts is observed within 6 h. However, at 2 days after administration of Sulfur Mustard adducts are still detectable in most of the organs studied. The intravenous toxicokinetics of Sulfur Mustard were also studied in the marmoset at a dose corresponding with 1 LD50 in the hairless guinea pig. The results obtained sofar will be discussed.
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standard operating procedure for immunuslotblot assay for analysis of dna Sulfur Mustard adducts in human blood and skin
Journal of Analytical Toxicology, 2004Co-Authors: G P Van Der Schans, H P Benschop, Roos H Marsgroenendijk, L P A De Jong, Daan NoortAbstract:A standard operating procedure has been developed for an immunoslotblot assay of Sulfur Mustard adducts to DNA in human blood and skin for use in a field laboratory. A minimum detectable level of exposure of human blood in vitro (> or = 50 nM) Sulfur Mustard is feasible with the assay. In the case of human skin, a 1 s exposure to saturated Sulfur Mustard vapor (830 mg/m(-3)) could still be detected.
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diagnosis and dosimetry of exposure to Sulfur Mustard development of a standard operating procedure for mass spectrometric analysis of haemoglobin adducts exploratory research on albumin and keratin adducts
Journal of Applied Toxicology, 2001Co-Authors: Daan Noort, A. Fidder, Albert G Hulst, Leo P A De Jong, H P BenschopAbstract:Experiments were carried out to develop a standard operating procedure for analysis of Sulfur Mustard adducts to the N-terminal valine in haemoglobin and to explore adduct formation with albumin and keratin. In the first approach, gas chromatography-negative chemical ionization/mass spectrometry (GC-NCI/MS) of the thiohydantoin sample subsequent to the modified Edman degradation was performed using a thermodesorption/cold trap (TCT) injection technique (detection limit for in vitro exposure of human blood to Sulfur Mustard: 30 nM). In the second approach, the crude thiohydantoin sample was purified by solid-phase extraction procedures. In the third approach, the procedure was shortened significantly by performing the Edman degradation for 2 h at 60°C. Upon exposure of human blood to various concentrations of [14C]Sulfur Mustard, ca. 20% was covalently bound to albumin. One of the tryptic fragments (T5 containing an alkylated cysteine (HETE-(A-L-V-L-I-A-F-A-Q-Y-L-Q-Q-C-P-F-E-D-H-V-K); MW 2536 Da) could be detected sensitively with liquid chromatography/tandem mass spectrometry analysis (detection limits: ≥15 pg absolute and 1 μM for in vitro exposure of human blood). Upon exposure of human callus (suspensions in 0.9% NaCl; 500 mg ml-1) to various concentrations of [14C]Sulfur Mustard we found 15-20% of the added radioactivity covalently bound to keratin. Upon incubation with base, 80% of the bound radioactivity was split off as [14C]thiodiglycol. This result opens the way for sensitive mass spectrometric detection of Sulfur Mustard exposure of skin by gas chromatography/mass spectrometry of (derivatized) thiodiglycol. Copyright © 2000 John Wiley & Sons, Ltd.
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toxicokinetics of Sulfur Mustard and its dna adducts in the hairless guinea pig
Drug and Chemical Toxicology, 1998Co-Authors: J P Langenberg, Hendrik C Trap, Willem C Kuijpers, H P M Van Helden, G P Van Der Schans, H E T Spruit, Roos H Marsgroenendijk, H C M Van Dijkknijnenburg, H P BenschopAbstract:In order to provide a quantitative basis for pretreatment and therapy of intoxications with Sulfur Mustard (SM) the toxicokinetics of this agent as well as its major DNA-adduct were studied in male hairless guinea pigs for the intravenous, respiratory and percutaneous routes. the study comprised measurement of the concentration-time course of SM in blood and measurement of the concentrations of intact SM and its adduct to guanine in various tissues at several time points after administration of, or exposure to SM. SM was analyzed in blood and tissues by gas chromatography with automated thermodesorption injection and mass-spectrometric detection. DNA-adducts were measured via an immuno-slot-blot method.In contrast with nerve agents of the phosphofluoridate type, SM partitions strongly to various organs, especially the lung, spleen, liver and bone marrow. the respiratory toxicity of SM appears to be local, rather than systemic. Surprisingly, the maximum concentration of SM in blood upon percutaneous exposu...
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immunochemical detection of adducts of Sulfur Mustard to dna of calf thymus and human white blood cells
Chemical Research in Toxicology, 1994Co-Authors: G P Van Der Schans, A. Fidder, H P Benschop, Roos H Marsgroenendijk, A G Scheffer, R A BaanAbstract:As part of a program to develop methods for dosimetry of exposure to Sulfur Mustard, we developed immunochemical methods for the detection of the major adduct, N7-[2-[(hydroxyethyl)thio]ethyl]guanine (N7-HETE-Gua), formed after alkylation of DNA with Sulfur Mustard. After immunization of rabbits with calf thymus DNA treated with Sulfur Mustard, we obtained the antiserum W7/10 with a high specificity for DNA adducts of Sulfur Mustard. With this serum, a competitive enzyme-linked immunosorbent assay was developed in which Sulfur Mustard adducts to DNA could be detected with a minimum detectable amount of 1-5 fmol per well and a selectivity that allows detection of one N7-HETE-Gua among 5 x 10(6) unmodified nucleotides in single-stranded DNA. The complications that arise to isolate double-stranded DNA from biological samples and to make the DNA single-stranded without destruction of the Sulfur Mustard adducts result in about a 20-fold higher limit for adduct detection in DNA from human blood than in single-stranded DNA. Presently, adducts in white blood cells can be detected after exposure of human blood to Sulfur Mustard concentrations > or = 2 microM. We synthesized N7-HETE-GMP for use as a hapten to generate monoclonal antibodies against this adduct. After immunization of mice with this adduct coupled to the carrier protein keyhole limpet hemocyanin we obtained several hybridomas producing monoclonal antibodies that recognize N7-HETE-Gua, containing an intact imidazolium ring. The sensitivity of the competitive ELISA with the monoclonal antibodies was comparable to that of the assays performed with the rabbit antiserum.(ABSTRACT TRUNCATED AT 250 WORDS)
Jincai Zhao - One of the best experts on this subject based on the ideXlab platform.
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sensitive discrimination of nerve agent and Sulfur Mustard simulants using fluorescent coassembled nanofibers with forster resonance energy transfer enhanced photostability and emission
Analytical Chemistry, 2019Co-Authors: Wei Xiong, Yanjun Gong, Yanke Che, Jincai ZhaoAbstract:In this work, highly sensitive discrimination of nerve agent and Sulfur Mustard simulants is achieved by using photostable and fluorescent coassembled nanofibers from molecules 1 and 2. We demonstrate that the introduction of 2 as a Forster resonance energy transfer (FRET) acceptor not only enhances the photostability and emission efficiency compared to individual 1 nanofibers but also induces different binding interactions between analytes and 1–2 coassembled nanofibers and thereby distinct fluorescence quenching behaviors used for the discrimination of nerve agent and Sulfur Mustard simulants. Our findings represent an important advance toward sensitive detection and discrimination of chemical warfare agents (CWAs).
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Sensitive Discrimination of Nerve Agent and Sulfur Mustard Simulants Using Fluorescent Coassembled Nanofibers with Förster Resonance Energy Transfer-Enhanced Photostability and Emission
2019Co-Authors: Wei Xiong, Yanjun Gong, Yanke Che, Jincai ZhaoAbstract:In this work, highly sensitive discrimination of nerve agent and Sulfur Mustard simulants is achieved by using photostable and fluorescent coassembled nanofibers from molecules 1 and 2. We demonstrate that the introduction of 2 as a Förster resonance energy transfer (FRET) acceptor not only enhances the photostability and emission efficiency compared to individual 1 nanofibers but also induces different binding interactions between analytes and 1–2 coassembled nanofibers and thereby distinct fluorescence quenching behaviors used for the discrimination of nerve agent and Sulfur Mustard simulants. Our findings represent an important advance toward sensitive detection and discrimination of chemical warfare agents (CWAs)
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Ultrasensitive Detection of Sulfur Mustard via Differential Noncovalent Interactions
2019Co-Authors: Changkun Qiu, Wei Xiong, Yanjun Gong, Jincai Zhao, Xiaoling Liu, Chuanqin Cheng, Yongxian Guo, Chen Wang, Yanke CheAbstract:In this work, we fabricate two types of hierarchical microspheres, i.e., one coassembled from two fluorene-based oligomers (1 and 2) and one self-assembled from a fluorene-based oligomer (1), for ultrasensitive and selective detection of trace Sulfur Mustard (SM) vapor. On the basis of distinct fluorescence responses of 1–2 coassembled and individual 1 hierarchical microspheres that originate from differential noncovalent interactions between analytes and these sensors, SM vapor can be ultrasensitively detected (30 ppb) and easily discriminated from various sulfides and other potential interferents. Our work that utilizes differential noncovalent interactions to give sensitive and selective fluorescence response patterns represents a new detection approach for SM and other hazardous chemicals
Robert P Casillas - One of the best experts on this subject based on the ideXlab platform.
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increased expression of the endocannabinoid system in mouse skin following exposure to Sulfur Mustard and nitrogen Mustard mechlorethamine
The FASEB Journal, 2016Co-Authors: Irene Wohlman, Donald R Gerecke, Robert P Casillas, Gabriella M Composto, Ned D Heindel, Laurie B JosephAbstract:Vesicants including Sulfur Mustard (SM, bis(2-chloroethyl) sulfide) and nitrogen Mustard (NM, bis(2-chloroethyl)methylamine) are highly reactive bifunctional alkylating agents that target the skin....
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regulation of hsp27 and hsp70 expression in human and mouse skin construct models by caveolae following exposure to the model Sulfur Mustard vesicant 2 chloroethyl ethyl sulfide
Toxicology and Applied Pharmacology, 2011Co-Authors: Adrienne T Black, Donald R Gerecke, Patrick J Hayden, Robert P Casillas, Patrick J SinkoAbstract:Dermal exposure to the vesicant Sulfur Mustard causes marked inflammation and tissue damage. Basal keratinocytes appear to be a major target of Sulfur Mustard. In the present studies, mechanisms mediating skin toxicity were examined using a mouse skin construct model and a full-thickness human skin equivalent (EpiDerm-FT™). In both systems, administration of the model Sulfur Mustard vesicant, 2-chloroethyl ethyl sulfide (CEES, 100-1000μM) at the air surface induced mRNA and protein expression of heat shock proteins 27 and 70 (Hsp27 and Hsp70). CEES treatment also resulted in increased expression of caveolin-1, the major structural component of caveolae. Immunohistochemistry revealed that Hsp27, Hsp70 and caveolin-1 were localized in basal and suprabasal layers of the epidermis. Caveolin-1 was also detected in fibroblasts in the dermal component of the full thickness human skin equivalent. Western blot analysis of caveolar membrane fractions isolated by sucrose density centrifugation demonstrated that Hsp27 and Hsp70 were localized in caveolae. Treatment of mouse keratinocytes with filipin III or methyl-β-cyclodextrin, which disrupt caveolar structure, markedly suppressed CEES-induced Hsp27 and Hsp70 mRNA and protein expression. CEES treatment is known to activate JNK and p38 MAP kinases; in mouse keratinocytes, inhibition of these enzymes suppressed CEES-induced expression of Hsp27 and Hsp70. These data suggest that MAP kinases regulate Hsp 27 and Hsp70; moreover, caveolae-mediated regulation of heat shock protein expression may be important in the pathophysiology of vesicant-induced skin toxicity.
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mechanisms mediating the vesicant actions of Sulfur Mustard after cutaneous exposure
Toxicological Sciences, 2010Co-Authors: Michael P Shakarjian, Debra L. Laskin, Patrick J Sinko, Diane E Heck, Joshua P Gray, Donald R Gerecke, Robert P Casillas, Ned D Heindel, Marion K Gordon, Jeffrey D LaskinAbstract:Sulfur Mustard (SM), a chemical weapon first employed during World War I, targets the skin, eyes, and lung. It remains a significant military and civilian threat. The characteristic response of human skin to SM involves erythema of delayed onset, followed by edema with inflammatory cell infiltration, the appearance of large blisters in the affected area, and a prolonged healing period. Several in vivo and in vitro models have been established to understand the pathology and investigate the mechanism of action of this vesicating agent in the skin. SM is a bifunctional alkylating agent which reacts with many targets including lipids, proteins, and DNA, forming both intra- and intermolecular cross-links. Despite the relatively nonselective chemical reactivity of this agent, basal keratinocytes are more sensitive, and blistering involves detachment of these cells from their basement membrane adherence zones. The sequence and manner in which these cells die and detach is still unresolved. Much has been discovered over the past two decades with respect to the mechanisms of SM-induced cytotoxicity and the intracellular and extracellular targets of this vesicant. In this review, the effects of SM exposure on the skin are described, as well as potential mechanisms mediating its actions. Successful therapy for SM poisoning will depend on following new mechanistic leads to develop drugs that target one or more of its sites of action.
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alterations of gene expression in Sulfur Mustard exposed skin topically treated with vanilloids
Journal of Toxicology-cutaneous and Ocular Toxicology, 2004Co-Authors: Carol L K Sabourin, Michael C Babin, James V Rogers, Mindy K Stonerock, Nancy A Niemuth, Robyn C Kiser, Stacy L Casbohm, John J Schlager, Robert P CasillasAbstract:Sulfur Mustard [bis(2‐chloroethyl)sulfide, SM] is a chemical warfare agent that penetrates the skin rapidly and causes extensive blistering. Using the mouse ear vesicant model (MEVM), we evaluated the effect of topically applied anti‐inflammatory agents (octyl homovanillamide and heptyl isovanillamide) on ear edema formation and gene expression following SM exposure. Relative ear weight and real‐time reverse transcriptase polymerase chain reaction of GM‐CSF, IL‐1β, and IL‐6 were used to evaluate the effects of octyl homovanillamide and heptyl isovanillamide. Both vanilloids significantly reduced SM‐induced edema. At the single dose and number of animals/group tested, octyl homovanillamide produced a trend of reduced mRNA levels; however, the reduction was not significant for GM‐CSF, IL‐1β, or IL‐6. Heptyl isovanillamide significantly reduced (p ≤ 0.05) GM‐CSF, IL‐1β, and IL‐6 mRNA levels. These results show that octyl homovanillamide and heptyl isovanillamide reduce skin edema and heptyl isovanillamide si...
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systemic administration of candidate antivesicants to protect against topically applied Sulfur Mustard in the mouse ear vesicant model mevm
Journal of Applied Toxicology, 2001Co-Authors: Michael C Babin, Karen M Ricketts, J P Skvorak, M Y Gazaway, Larry W Mitcheltree, Robert P CasillasAbstract: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 μl 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.
