Efficacy of soap and water-based skin decontamination using in vitro animal models: A systematic review

Water and/or soap and water solutions have historically been used as first-line decontamination strategies for a wide variety of dermal contaminants from workplace exposure, environmental pesticides, and civilian chemical warfare. Although water and/or soap and water solutions are often considered a gold standard of decontamination, many studies have found other decontamination methods to be superior. This systematic review summarizes the available data on in vitro animal models contaminated with a various chemicals and their decontamination with water and/or soap and water solutions using in vitro animal models. A comprehensive literature search was performed using Concordance, Embase, PubMed, Medline, Web of Science, and Google Scholar to find in vitro animal studies that provided data on dermal decontamination using water and/or soap and water solutions. Five studies were included that analyzed 11 contaminants across two in vitro animal models (rats and pigs). Water alone was used as a decontamination method for 63.6% of the contaminants (n = 7/11) and water and soap solutions for decontamination in 54.6% of contaminants (n = 6/11). Water alone provided incomplete contaminant removal of five of seven contaminants studied; soap and water did not show significant difference in decontamination when compared with other solutions for all four contaminants and was superior to water for both contaminants studied. Water and/or soap and water are used as decontamination strategies for a variety of dermal contamination events, but for many contaminants, they do not provide complete contamination when compared with newer decontamination solutions studied with in vitro animal models.     

Efficacy of water skin decontamination in vivo in humans: A systematic review

With the constant possibility of occupational exposures, chemical warfare, and targeted attacks, increased attention has been given to determining effective and timely dermal decontamination strategies. This systematic review summarises experimental studies reporting decontamination with water-based solutions of dermal chemical contaminants with in vivo human data. Embase, MEDLINE, PubMed, Web of Science, and Google Scholar databases were comprehensively searched using search terms (“cutaneous” or “skin” or “dermal” or “percutaneous”) and (“decontamination” or “decontaminant” or “skin decontamination”) to include 10 studies, representing 18 chemical contaminants, 199 participants, and 351 decontamination outcomes. Three studies included data from decontamination with water (10.8%, n = 38/351 decontamination outcomes), seven with soap and water (68.4%, n = 240/351 decontamination outcomes), and two with 10% isopropanol distilled water (20.8%, n = 73/351 decontamination outcomes). Results of dermal decontamination using water showed complete decontamination (CD) outcomes in 52.6% (n = 20/38) and partial decontamination (PD) in 47.4% (n = 18/38); using soap and water showed PD outcomes in 92.9% (n = 223/240) and minimal to no effect in 7.1% (n = 17/240); and using 10% isopropanol distilled water achieved PD outcomes in 100.0% (n = 73/73). Available data show that decontamination with water, soap and water, and 10% isopropanol distilled water is incomplete. Much remains to be learned about decontamination of the large variety of chemical contaminants including a range of molecular weights, lipid and water solubilities, melting points, volatility, and hydrogen bonds, as well as clinically relevant anatomic sites. A major void exists in data confirming or denying the completeness of decontamination by measuring absorption and excretion. The development of effective decontamination solutions is of high priority.     

Chemical warfare agent simulants for human volunteer trials of emergency decontamination: A systematic review

Incidents involving the release of chemical agents can pose significant risks to public health. In such an event, emergency decontamination of affected casualties may need to be undertaken to reduce injury and possible loss of life. To ensure these methods are effective, human volunteer trials (HVTs) of decontamination protocols, using simulant contaminants, have been conducted. Simulants must be used to mimic the physicochemical properties of more harmful chemicals, while remaining non‐toxic at the dose applied. This review focuses on studies that employed chemical warfare agent simulants in decontamination contexts, to identify those simulants most suitable for use in HVTs of emergency decontamination. Twenty‐two simulants were identified, of which 17 were determined unsuitable for use in HVTs. The remaining simulants (n = 5) were further scrutinized for potential suitability according to toxicity, physicochemical properties and similarities to their equivalent toxic counterparts. Three suitable simulants, for use in HVTs were identified; methyl salicylate (simulant for sulphur mustard), diethyl malonate (simulant for soman) and malathion (simulant for VX or toxic industrial chemicals). All have been safely used in previous HVTs, and have a range of physicochemical properties that would allow useful inference to more toxic chemicals when employed in future studies of emergency decontamination systems.     

皮肤洗消剂PF2009对化学毒剂的消毒作用

目的通过检测皮肤洗消剂PF2009对化学毒剂的体外消毒效率,对皮肤洗消剂PF2009的消毒效果进行评价。方法将皮肤洗消剂PF2009按比例分别同梭曼（GD）、维埃克斯（vx）、芥子气（HD）混合,采用色谱分析法或T-135法于不同作用时间检测化学毒剂的剩余量。将皮肤洗消剂PF2009及其基质分别按相同比例与GD、VX或HD相互作用．1h后利用反应混合物进行在体动物实验．染毒后6d内观察动物存活情况,进行乙酰胆碱酯酶（ACHE）活性检测．或通过观察皮肤损伤面积及组织病理学变化等指标评价皮肤洗消剂PF2009的消毒效果。结果洗消剂对VX和GD具有快速、高效的消毒效果,在洗消剂与两毒剂分别按照体积比50：1进行消毒时,相互作用10min后,其消毒效率均大于99％：洗消剂对HD也具有较好的消毒效果,混匀后静置10min,消毒率达到80％以上,静置60min,其消毒率达到94％。毒剂与洗消液有效成分的摩尔比为1：10时。混匀60rain后GD消毒产物按照GD剂量4．54、9．0mg／kg（以初始加入GD量计）腹腔注射（ip）家兔。VX消毒产物3．34mg／ks（以初始加入VX量计）ip家兔,6d之内家兔全部存活,血液AChE活性均为正常对照的90％以上．而对应的基质对照组动物全部死亡。HD与PF2009消毒产物1mg／cm。皮肤染毒组同HD基质消毒对照组相比皮肤损伤明显减轻。结论皮肤洗消剂PF2009在体外对毒剂具有很好的消毒效果。     

Preliminary evaluation of military,commercial and novel skin decontamination products against a chemical warfare agent simulant (methyl salicylate)

Rapid decontamination is vital to alleviate adverse health effects following dermal exposure to hazardous materials. There is an abundance of materials and products which can be utilised to remove hazardous materials from the skin. In this study, a total of 15 products were evaluated, 10 of which were commercial or military products and five were novel (molecular imprinted) polymers. The efficacies of these products were evaluated against a 10?µl droplet of ¹⁴C-methyl salicylate applied to the surface of porcine skin mounted on static diffusion cells. The current UK military decontaminant (Fuller’s earth) performed well, retaining 83% of the dose over 24?h and served as a benchmark to compare with the other test products. The five most effective test products were Fuller’s earth (the current UK military decontaminant), Fast-Act® and three novel polymers [based on itaconic acid, 2-trifluoromethylacrylic acid and N,N-methylenebis(acrylamide)]. Five products (medical moist-free wipes, 5% FloraFree? solution, normal baby wipes, baby wipes for sensitive skin and Diphotérine?) enhanced the dermal absorption of ¹⁴C-methyl salicylate. Further work is required to establish the performance of the most effective products identified in this study against chemical warfare agents.     

Development of haemostatic decontaminants for the treatment of wounds contaminated with chemical warfare agents. 1: Evaluation of in vitro clotting efficacy in the presence of certain contaminants

The treatment of penetrating, haemorrhaging injuries sustained within a hazardous environment may be complicated by contamination with toxic chemicals. There are currently no specific medical countermeasures for such injuries. Haemostats with an absorbent mechanism of action have the potential to simultaneously stop bleeding and decontaminate wounds. However, a primary requirement of a ‘haemostatic decontaminant’ is the retention of clotting function in the presence of chemical contaminants. Thus, the aim of this study was to investigate the haemostatic efficacy of seven commercially available haemostats in the presence of toxic chemicals (soman, VX, sulphur mustard, petrol, aviation fuel and motor oil). Clot viscosity was assessed ex vivo using thrombelastography following treatment of pig blood with: (i) toxic chemical; (ii) haemostat; or (iii) haemostat in combination with toxic chemical. Several contaminants (VX, petrol and GD) were found to be pro‐haemostatic and none had an adverse effect on the rate with which the test products attained haemostasis. However, the total clot strength for blood treated with certain haemostats in the presence of sulphur mustard, soman and petrol was significantly decreased. Three test products failed to demonstrate haemostatic function in this ex vivo (thrombelastography) model; this was tentatively ascribed to the products achieving haemostasis through a tamponade mechanism of action, which can only be replicated using in vivo models. Overall, this study has identified a number of commercial products that may have potential as haemostatic decontaminants and warrant further investigation to establish their decontaminant efficacy. Copyright © 2014 John Wiley & Sons, Ltd.     

Development of haemostatic decontaminants for the treatment of wounds contaminated with chemical warfare agents. 2: Evaluation of in vitro topical decontamination efficacy using undamaged skin

The risk of penetrating, traumatic injury occurring in a chemically contaminated environment cannot be discounted. Should a traumatic injury be contaminated with a chemical warfare (CW) agent, it is likely that standard haemostatic treatment options would be complicated by the need to decontaminate the wound milieu. Thus, there is a need to develop haemostatic products that can simultaneously arrest haemorrhage and decontaminate CW agents. The purpose of this study was to evaluate a number of candidate haemostats for efficacy as skin decontaminants against three CW agents (soman, VX and sulphur mustard) using an in vitro diffusion cell containing undamaged pig skin. One haemostatic product (WoundStat?) was shown to be as effective as the standard military decontaminants Fuller's earth and M291 for the decontamination of all three CW agents. The most effective haemostatic agents were powder‐based and use fluid absorption as a mechanism of action to sequester CW agent (akin to the decontaminant Fuller's earth). The envisaged use of haemostatic decontaminants would be to decontaminate from within wounds and from damaged skin. Therefore, WoundStat? should be subject to further evaluation using an in vitro model of damaged skin. Copyright © 2014 Crown copyright. Journal of Applied Toxicology © 2014 John Wiley & Sons, Ltd.     

Development of haemostatic decontaminants for treatment of wounds contaminated with chemical warfare agents. 3: Evaluation of in vitro topical decontamination efficacy using damaged skin

Previous studies have demonstrated that haemostatic products with an absorptive mechanism of action retain their clotting efficiency in the presence of toxic materials and are effective in decontaminating chemical warfare (CW) agents when applied to normal, intact skin. The purpose of this in vitro study was to assess three candidate haemostatic products for effectiveness in the decontamination of superficially damaged porcine skin exposed to the radiolabelled CW agents, soman (GD), VX and sulphur mustard (HD). Controlled physical damage (removal of the upper 100 μm skin layer) resulted in a significant enhancement of the dermal absorption of all three CW agents. Of the haemostatic products assessed, WoundStat™ was consistently the most effective, being equivalent in performance to a standard military decontaminant (fuller's earth). These data suggest that judicious application of haemostatic products to wounds contaminated with CW agents may be a viable option for the clinical management of casualties presenting with contaminated, haemorrhaging injuries. Further studies using a relevant animal model are required to confirm the potential clinical efficacy of WoundStat™ for treating wounds contaminated with CW agents. Copyright © 2017 John Wiley & Sons, Ltd.     

A review of the efficacy of easily accessible dry decontaminants for human chemical contamination

Soap and water are often considered the gold standard for dermal decontamination. However, recent systematic reviews have shown that these methods often result in incomplete decontamination and may even induce contaminant absorption due to the “wash-in” effect. Therefore, it is important to gain insight on other decontamination methods. A literature search was done using PubMed to find experimental studies relating to dry decontamination performed with readily available items. Seven studies met eligibility criteria, and the study model, dry decontaminant, method of dry decontamination, method of analyzing decontamination, and main conclusions from each study were extracted, summarized, and compared. Important conclusions include that all studies investigated found that dry decontamination yielded decreases in contamination. In addition, it was shown by multiple studies that not only the decontaminant, but the manner in which it is used (method used [blotting, rubbing, etc.], amount used, and whether decontamination instructions are provided to exposed individuals) is vital to success. Finally, in all four studies that investigated wet and dry decontamination combination protocols, combinations were more efficacious than dry decontamination alone. However, this means that dry improvised decontamination can be performed while waiting for the deployment and arrival of further formal decontaminants. These conclusions deserve consideration in the event that universal decontamination guidelines are designed. However, more studies are required in order to draw definitive conclusions regarding the important topic of dermal decontamination.     

An in vitro and in vivo evaluation of the efficacy of recombinant human liver prolidase as a catalytic bioscavenger of chemical warfare nerve agents

In this study, we determined the ability of recombinant human liver prolidase to hydrolyze nerve agents in vitro and its ability to afford protection in vivo in mice. Using adenovirus containing the human liver prolidase gene, the enzyme was over expressed by 200- to 300-fold in mouse liver and purified to homogeneity by affinity and gel filtration chromatography. The purified enzyme hydrolyzed sarin, cyclosarin and soman with varying rates of hydrolysis. The most efficient hydrolysis was with sarin, followed by soman and by cyclosarin {apparent k_cat/K_m [(1.9?±?0.3), (1.7?±?0.2), and (0.45?±?0.04)]?×?10^5?M^?1?min^?1, respectively}; VX and tabun were not hydrolyzed by the recombinant enzyme. The enzyme hydrolyzed P (+) isomers faster than the P (?) isomers. The ability of recombinant human liver prolidase to afford 24 hour survival against a cumulative dose of 2?×?LD₅₀ of each nerve agent was investigated in mice. Compared to mice injected with a control virus, mice injected with the prolidase expressing virus contained (29?±?7)-fold higher levels of the enzyme in their blood on day 5. Challenging these mice with two consecutive 1?×?LD₅₀ doses of sarin, cyclosarin, and soman resulted in the death of all animals within 5 to 8?min from nerve agent toxicity. In contrast, mice injected with the adenovirus expressing mouse butyrylcholinesterase, an enzyme which is known to afford protection in vivo, survived multiple 1?×?LD₅₀ challenges of these nerve agents and displayed no signs of toxicity. These results suggest that, while prolidase can hydrolyze certain G-type nerve agents in vitro, the enzyme does not offer 24 hour protection against a cumulative dose of 2?×?LD₅₀ of G-agents in mice in vivo.     

Efficacy studies of Reactive Skin Decontamination Lotion,M291 Skin Decontamination Kit, 0.5% bleach, 1% soapy water,and Skin Exposure Reduction Paste Against Chemical Warfare Agents,Part 1: Guinea pigs challenged with VX

Objective: This report, first in a series of five, directly compares the efficacy of 4 decontamination products and Skin Exposure Reduction Paste Against Chemical Warfare Agents (SERPACWA) in the haired guinea pig model following exposure to VX.

Methods: In all experiments, guinea pigs were close-clipped and given anesthesia. In the decontamination experiments, the animals were challenged with VX and decontaminated after a 2-minute delay for the standard procedure or at longer times for the delayed-decontamination experiments. Skin Exposure Reduction Paste Against Chemical Warfare Agents was applied as a thin coating (0.1?mm thick), allowed to dry for 15 minutes, and challenged with VX. After a 2-hour challenge, any remaining VX was blotted off the animal, but no additional decontamination was done. Positive control animals were challenged with VX in the same manner as the treated animals, except that they received no treatment. In addition, the positive control animals were always challenged with 5% VX in isopropyl alcohol (IPA) solution, whereas the treatment animals received either neat (undiluted) VX or 5% VX in IPA solution. All animals were observed during the first 4 hours and again at 24 hours after exposure for signs of toxicity and death. The protective ratio (PR, defined as the median lethal dose [LD₅₀] of the treatment group divided by the LD₅₀ of the untreated positive control animals) was calculated from the probit dose–response curves established for each treatment group and nontreated control animals. Significance in this report was defined as p <?.05.

Results: In the standard 2-minute neat VX decontamination experiments, the calculated PRs for Reactive Skin Decontamination Lotion (RSDL), 0.5% bleach, 1% soapy water, and the M291 Skin Decontamination Kit (SDK) were 66, 17, 16, and 1.1, respectively. Reactive Skin Decontamination Lotion was by far the most effective decontamination product tested and was significantly better than any of the other products. Bleach and soapy water provided equivalent and good (PR > 5) protection. They were both significantly better than the M291 SDK. The M291 SDK did not provide significant protection compared with positive controls. In the neat VX delayed-decontamination experiments, the calculated LT₅₀ (the delayed-decontamination time at which 50% of the animals died in the test population following a 5-LD₅₀ challenge) values for RSDL, 0.5% bleach, and 1% soapy water were 31, 48, and 26 minutes, respectively. The results showed that SERPACWA provided significant, but modest (PR < 5), protection against neat VX, with a PR of 2.1.

Conclusions: Several conclusions can be drawn from this study: 1) RSDL provided superior protection against VX compared with the other products tested; 2) 0.5% bleach and 1% soapy water were less effective than RSDL, but still provided good protection against VX; 3) the M291 SDK was the least effective decontamination product and did not provide significant protection against VX; 4) the agent was observed to streak when using the M291 SDK, and efficacy may improve if the agent is first blotted, followed by wiping with a new or clean part of the M291 SDK pad; 5) RSDL, 0.5% bleach, and 1% soapy water provided significant protection against a 5-LD₅₀ challenge of VX, even when decontamination was delayed for up to about 30 minutes; and 6) SERPACWA provided significant, but modest, protection against VX.     

Advances in toxicology and medical treatment of chemical warfare nerve agents

Organophosphorous (OP) Nerve agents (NAs) are known as the deadliest chemical warfare agents. They are divided into two classes of G and V agents. Most of them are liquid at room temperature. NAs chemical structures and mechanisms of actions are similar to OP pesticides, but their toxicities are higher than these compounds. The main mechanism of action is irreversible inhibition of Acetyl Choline Esterase (AChE) resulting in accumulation of toxic levels of acetylcholine (ACh) at the synaptic junctions and thus induces muscarinic and nicotinic receptors stimulation. However, other mechanisms have recently been described. Central nervous system (CNS) depression particularly on respiratory and vasomotor centers may induce respiratory failure and cardiac arrest. Intermediate syndrome after NAs exposure is less common than OP pesticides poisoning. There are four approaches to detect exposure to NAs in biological samples: (I) AChE activity measurement, (II) Determination of hydrolysis products in plasma and urine, (III) Fluoride reactivation of phosphylated binding sites and (IV) Mass spectrometric determination of cholinesterase adducts. The clinical manifestations are similar to OP pesticides poisoning, but with more severity and fatalities. The management should be started as soon as possible. The victims should immediately be removed from the field and treatment is commenced with auto-injector antidotes (atropine and oximes) such as MARK I kit. A 0.5% hypochlorite solution as well as novel products like M291 Resin kit, G117H and Phosphotriesterase isolated from soil bacterias, are now available for decontamination of NAs. Atropine and oximes are the well known antidotes that should be infused as clinically indicated. However, some new adjuvant and additional treatment such as magnesium sulfate, sodium bicarbonate, gacyclidine, benactyzine, tezampanel, hemoperfusion, antioxidants and bioscavengers have recently been used for OP NAs poisoning.     

Detection of chemical threat agents in drinking water by an early warning real-time biomonitor

Having a safe water supply for civilian organizations and military personnel is an important objective to avoid toxic contamination of civilians and soldiers. Chemical warfare (CW) agents, especially organophosphorous nerve compounds, are the most toxic of known chemical agents. The Daphnia Toximeter system is a continuously working test system that uses Daphnia magna as a sensitive organism for monitoring drinking water. Both small doses (allowable for short-term water ingestion) and graduated higher concentrations induced toxic reactions in the Daphnia Toximeter system, leading to alarms sounding. The system is sensitive to a wide range of CW agents and their hydrolysis products. Concentrations below acute human toxicity can be discovered in a very short time, with the actual time depending on the concentrations applied. In every case alarms were triggered within 2 h at concentrations in water low enough for that water to be allowed for use as drinking water in exceptional conditions.     

In vitro skin decontamination model: comparison of salicylic acid and aminophylline

Objective: This study compared three model decontaminant solutions (distilled water, 10% distilled water and soap and methanol) for their ability to remove salicylic acid and aminophylline from an in vitro skin model.

Materials and methods: Human abdominal skin was dosed with 20?µL of either [¹⁴C]-aminophylline or [¹⁴C]-salicylic acid on 1?cm² per skin. After each exposure time (5, 30 and 60?min post-dosing, respectively), surface skin was washed three times with each solution and tape stripped 10 times. Wash solutions, tape strips, receptor fluid and remaining skin were then analyzed with liquid scintillation counting to quantify the amount of salicylic acid and aminophylline.

Results: Total mass balance recovery for each chemical at three time exposure points was between 73.6 and 101.5%, except at 60?min where aminophylline was only 42.5%. Majority of salicylic acid and aminophylline were recovered from washing solution when compared to stratum corneum, epidermis, dermis, surrounding skin and receptor fluid.

Conclusion: The three tested decontaminates possessed similar effectiveness in removing lipophilic and hydrophilic chemicals from the skin. Due to diminishing decontamination efficacy with time, it is suggested that skin should be washed as soon as possible following contamination to minimize percutaneous penetration and the deleterious effects associated with skin reservoir content.     

Percutaneous penetration and absorption of parathion using human and pig skin models in vitro and human skin grafted onto nude mouse skin model in vivo

This study determined and compared the percutaneous penetration and absorption of an organophosphorus (OP) pesticide, parathion (PA), using three experimental skin models: namely the human abdominal- and pig-ear skin in vitro models and the Human Skin grafted onto a nude mouse (HuSki) in vivo model. The percentage of topically applied dose absorbed and the doses present in the stratum corneum and skin were systematically determined at 24 h under similar experimental conditions. The three experimental skin models were first compared. Then, the advantages of the HuSki model for in vivo PA skin absorption studies were evaluated compared with the pig in vivo model previously used by others. Lastly, the relevance of each skin model to predict the permeability of human skin to PA in vivo was assessed by comparing our results with previously published in vivo human volunteer values. It was demonstrated that (a) pig-ear skin is relevant for predicting the in vitro human abdominal skin absorption taking into account a 2-3 times higher skin permeability to PA, (b) using ethanol as the vehicle, the absorption of PA was 4-5 times higher in the HuSki model than in the pig model but supports the usefulness of the HuSki model to easy mass balance studies, (c) both human in vitro and HuSki models closely predict the in vivo human volunteer absorption at 24 h when acetone is used as a vehicle but the HuSki model overcomes the known limitations of in vitro models for studying the fate of PA in the different skin layers after topical application.     

Percutaneous penetration and distribution of VX using in vitro pig or human excised skin validation of demeton-S-methyl as adequate simulant for VX skin permeation investigations

The organophosphorus (OP) chemical warfare V agent O-ethyl-S-[2(di-isopropylamino)ethyl] methyl phosphonothioate (VX), is a highly toxic compound which mainly penetrates the body via percutaneous pathways. Hence, the following prerequisite: to ascertain compound absorption and percutaneous profile distribution with a view to further assessing the efficacy of topical skin protectants. We first selected the most appropriate receptor fluid to carry out in vitro VX absorption experiments, namely: Hanks's Balanced Salt Solution (HBSS). After a 24-h topical exposure time lapse, we measured altogether the percentage of applied dose unabsorbed and absorbed, penetration rate, lag time, permeability coefficient (K(p)), and dose of VXeq present in skin. To such an end, we used full-thickness and split-thickness pig-ear or human abdominal skin membranes. Further, we scrutinised the potential use of two specific molecules as suitable surrogates for VX percutaneous penetration analyses: thus, we compared the present VX toxicokinetic parameters to earlier findings from our research unit, with respect to OP insecticides demethon-S-methyl (DSM) and paraoxon (POX). Within the framework of our study, we wish to highlight the following evidence: (a) pig-ear skin proves a relevant model to predict in vitro human abdominal skin, taking into account a 2-fold higher skin permeability to VXeq; (b) both full or split-thickness skin membranes may be used indiscriminately to gauge penetration rate and absorbed dose; (c) DSM applied on full-thickness pig-ear skin is the most relevant model to mimic the in vitro VX absorption through full-thickness skin model.     

Using pharmacokinetics and pharmacodynamics to optimise dosing of antifungal agents in critically ill patients: a systematic review

The prevalence of invasive fungal infections (IFIs) caused by Candida spp. is increasing in critically ill patients. Recent development of new antifungal agents has significantly contributed to the successful treatment of IFIs. However, the pharmacokinetics of antifungal agents can be altered in a number of disease states, including critical illness. Therefore, doses established in healthy volunteers and other patient groups may not be appropriate for the critically ill. Moreover, inadequate dosing may contribute to treatment failure and the emergence of resistance. This systematic review provides a critical analysis of the pharmacokinetics of antifungal agents in the critically ill and their relevance to dosing requirements in clinical practice. Based on the limited data available, dosing of some antifungal agents may have to be adjusted in critically ill patients with conserved renal function as well as in those requiring renal replacement therapy. Further research to confirm the appropriateness of current dosing strategies to attain the appropriate pharmacodynamic targets is recommended.     

Anticancer effects of cantharidin in A431 human skin cancer (Epidermoid carcinoma) cells in vitro and in vivo

Cantharidin (CTD), a potential anticancer agent of Traditional Chinese Medicine has cytotxic effects in different human cancer cell lines. The cytotoxic effects of CTD on A431 human skin cancer (epidermoid carcinoma) cells in vitro and in A431 cell xenograft mouse model were examined. In vitro, A431 human skin cell were treated with CTD for 24 and 48 h. Cell phase distribution, ROS production, Ca²⁺ release, Caspase activity and the level of apoptosis associated proteins were measured. In vivo, A431 cell xenograft mouse model were examined. CTD‐induced cell morphological changes and decreased percentage of viable A431 cells via G0/G1 phase arrest and induced apoptosis. CTD‐induced G0/G1 phase arrest through the reduction of protein levels of cyclin E, CDK6, and cyclin D in A431 cells. CTD‐induced cell apoptosis of A431 cells also was confirm by DNA gel electrophoresis showed CTD‐induced DNA fragmentation. CTD reduced the mitochondrial membrane potential and stimulated release of cytochrome c, AIF and Endo G in A431 cells. Flow cytometry demonstrated that CTD increased activity of caspase‐8, ?9 and ?3. However, when cells were pretreated with specific caspase inhibitors activity was reduced and cell viability increased. CTD increased protein levels of death receptors such as DR4, DR5, TRAIL and levels of the active form of caspase‐8, ?9 and ?3 in A431 cells. AIF and Endo G proteins levels were also enhanced by CTD. In vivo studies showed that CTD significantly inhibited A431 cell xenograft tumors in mice. Taken together, these in vitro and in vivo results provide insight into the mechanisms of CTD on cell growth and tumor production. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 723–738, 2017.     

Efficacy of metformin in the management of periodontitis: A systematic review and meta-analysis

Periodontitis is characterized by inflammation of the periodontium and leads to loss of teeth if untreated. Although a number of surgical and pharmacological options are available for the management of periodontitis, it still affects a large proportion of population. Recently, metformin (MF), an oral hypoglycemic, has been used to treat periodontitis. The aim of this review is to systematically evaluate the efficacy of MF in the treatment of periodontitis. An electronic search was carried out using the keywords ‘metformin’, ‘periodontal’ and ‘periodontitis’ via the PubMed/Medline, ISI Web of Science and Google Scholar databases for relevant articles published from 1949 to 2016. The addressed focused question was: ‘Is metformin effective in reducing bone loss in periodontitis? Critical review and meta-analysis were conducted of the results obtained in the selected studies. Following the removal of the duplicate results, the primary search resulted in 17 articles and seven articles were excluded based on title and abstract. Hence, 10 articles were read completely for eligibility. After exclusion of four irrelevant studies, six articles were included. The topical application of MF resulted in improved histological, clinical and radiographic outcomes. Additionally, results from the meta-analysis indicated that application of metformin improved the clinical and radiographic outcomes of scaling and root-planing, but at the same time heterogeneity was evident among the results. However, because of a lack of histological and bacterial studies, in addition to short follow-up periods and risk of bias, the long-term efficacy of MF in the treatment of bony defects is not yet ascertained. Further studies are needed to envisage the long-term efficacy of MF in the management of periodontitis.     

司美格鲁肽周制剂治疗成人超重和肥胖有效性与安全性的系统评价和Meta分析

目的：系统评价司美格鲁肽周制剂治疗成人超重和肥胖的有效性与安全性。方法：计算机检索PubMed、Embase、Cochrane Library、The ClinicalTrials.gov、中国知网、万方数据库、维普数据库,查找关于司美格鲁肽周制剂治疗成人超重和肥胖的随机对照试验（randomised controlled trials,RCTs）。由2名研究员独立筛选文献、提取资料,并进行方法学质量评价,应用RevMan 5.3软件进行Meta分析。结果：最终纳入7项RCTs,共计4 711例患者。Meta分析结果显示,与安慰剂组相比,司美格鲁肽可有效降低受试者体质量[MD=-10.75,95% CI （-13.22,-8.28）,P<0.001];提高减重>5%、10%和15%的患者分别占总体的比例[RR=2.29,95% CI （1.73,3.04）,P<0.001]、[RR=4.54,95% CI （2.94,7.02）,P<0.001]、[RR=6.91,95% CI （4.32,11.05）,P<0.001];降低身体质量指数[MD=-3.85,95% CI （-5.51,-2.19）,P<0.001];减小腰围[MD=-8.01,95% CI （-10.05,-5.97）,P<0.001];降低收缩压[MD=-3.88,95% CI （-4.93,-2.82）,P<0.001]和舒张压[MD=-1.79,95% CI （-2.95,-0.62）,P=0.003],差异均有统计学意义。司美格鲁肽总不良反应发生率与安慰剂组接近[RR=1.05,95% CI （1.00,1.10）,P=0.040];严重不良反应发生率高于安慰剂组,但差异无统计学意义[RR=1.49,95% CI （0.87,2.56）,P=0.150];胃肠道不良反应发生率显著高于安慰剂组,差异有统计学意义[RR=1.58,95% CI （1.41,1.78）,P<0.001]。结论：司美格鲁肽周制剂在成人超重和肥胖患者中的减重效果较好,但应警惕其胃肠道不良反应。