We will next discuss effective management of environmental risks from chemical substances. In 1997, the US Presidential/Congressional Commission on Risk Assessment and Risk Management proposed a six-stage framework for risk management. The six stages involve defining the problem and putting it in context, analyzing the risks associated with the problem in context, examining options for addressing the risks, making decisions about which options to implement, taking actions to implement the decisions, and conducting an evaluation of the actions. Other countries often reference these processes in evaluating new environmental risk management methods. As methods and procedures of evaluating risks of chemical substances caught the attention, research advanced in finding a common scale for evaluating environmental risks of which chemical substances affect human health to what extents. Once the environmental risk of each chemical substance is evaluated, we can then identify risk management of which chemical substance to prioritize and to reduce the risk to what level.

The magnitude of environmental risk from a chemical substance depends on the severity of health damage when exposed to the substance (e.g., exposure to benzene can cause leukemia in which case the worst scenario is death) and the amount of intake of the substance from the environment (e.g., the lifetime intake of benzene). In general, environmental risk evaluation proceeds in checking the hazards associated with the chemical substance, analyzing the relation of volume to reaction, measuring the amount of exposure, and assessing the risk, that is, first confirming the harm to health by the chemical substance and then evaluating how high the level of harm is to the health with the amount of intake, next the process of estimation to what level people take the substance from the environment, and last, judgment what level of health damages to expect at what level of exposure.

We now explain the four-step environmental risk evaluation in Uchiyama’s paper (Uchiyama 1996) with benzene. Benzene is produced from synthetic resin and other materials at the rate of about four million tons a year. Epidemiological studies of leukemia with workers in factories that use benzene as glue and animal experiments have confirmed that benzene is a carcinogenic hazardous material. The unit risk of benzene in terms of developing leukemia is the measure of the level increase in the risk of leukemia with lifetime intake of 1 microgram per 1 cubic meters. The volume-reaction relation, according to an overseas epidemiological study, estimates the unit risk of benzene at 3–7 for every 1 million persons. Measuring the benzene concentration in the air gives an estimate of exposure to benzene. If we calculate the environmental risk of benzene in Japan from its unit risk, concentration in the air, population, and average life, we can estimate the leukemia outbreak risk at several tens of people a year.

Significant improvements in the manufacturing environment and quality control standards have been achieved through the implementation of KVGMP. However, voluntary efforts by manufacturers are still needed to continue the application of KVGMP for the improvement of the quality of veterinary medicines. In particular, OCD showed a high noncompliance rate of about 3%. The Ministry of Agriculture, Food and Rural Affairs (MAFRA) of Korea is expecting to analyse the sales figures from the Korea Animal Health Products Association, and the NPMS assay results from QIA accordingly, to increase the statistical feasibility of the NPMS assessment results. The MAFRA is also expecting to increase the number of test samples for OCD, as they present relatively high noncompliance rates. It is also expected by MAFRA to reinforce testing during the vulnerable summer season. Proactive self-quality control by manufacturers for improved veterinary medicine quality must be promoted; while simultaneously, the efforts to establish an effective quality control system must continue as well.

Table 3 outlines the causes for noncompliance in veterinary medicines collected and tested between 2006 and 2016. From a total of 358 cases, 283 (79.1%) and 60 (16.8%) cases were deemed noncompliant owing to “insufficiency of major ingredient quantity” and “excess of major ingredient quantity”, respectively. Moreover, 3 (0.8%), 4 (1.1%), 3 (0.8%), and 5 (1.4%) cases were marked as “inadequate pH,” “abnormal characteristics,” “violation of marking standards,” and “others”, respectively.

1Food Animal Health and Management Program, University of Georgia, Athens, GA, USA, 2Alberta Beef Health Solutions, Picture Butte, AB, Canada, 3Department of Large Animal Medicine, University of Georgia College of Veterinary Medicine, Athens, GA, USA

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Brent Credille1, Sydney Crosby2, Roy Berghaus1, Steeve Giguere3

The goals of this study were to compare the efficacies of tulathromycin to enrofloxacin in cattle at high‐risk of developing BRD, and the prevalence of MDR strains of M. haemolytica before and after metaphylactic administration of each drug. Stocker calves (n=341) were randomly assigned to 2 treatment groups: enrofloxacin (n=172) and tulathromycin (n=169). 33.7% of calves receiving enrofloxacin required treatment for BRD within 45 days after arrival, compared to 18.3% of calves receiving tulathromycin. The odds of being diagnosed with BRD were ∼58% lower for calves receiving tulathromycin compared to those receiving enrofloxacin (P = 0.040). 10.5% of calves receiving enrofloxacin required more than one treatment, compared to 4.7% of calves receiving tulathromycin. The odds of requiring a second treatment were 60% lower for calves receiving tulathromycin compared to those receiving enrofloxacin. (P = 0.107). 12.2% of calves receiving enrofloxacin died during the 45‐day follow‐up period, compared to 10.1% of calves receiving tulathromycin (P = 0.592). In calves receiving enrofloxacin, M. haemolytica was cultured from 11.4% of calves sampled at arrival, and from 54.6% sampled at revaccination. In calves receiving tulathromycin, M. haemolytica was cultured from 10.8% of calves sampled at arrival, and from 48.7% sampled at revaccination. There was a significant effect of sampling occasion (P < 0.001) with both groups having higher prevalences of M. haemolytica at revaccination than at arrival. All calves in both groups had MDR strains at the time of revaccination, with the prevalence being significantly (P < 0.000) higher than at arrival.

1Hagyard Equine Medical Insititute, Paris, KY, USA, 2Equine Internal Medicine NC State Veterinary School, Raleigh, NC, USA, 3Department of Large Animal Medicine, University of Georgia College of Veterinary Medicine, Athens, GA, USA, 4Department of Large Animal Science University of Florida College of Veterinary Medicine, Gainesville, FL, USA, 5University of Kentucky/Consultant Director Al Shaqab Equine Veterinary Medical Centre, Lexington, KY, USA

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Nathan Slovis1, Nimet Browne2, Steeve Giguere3, Jorge Hernandez4, Mats Troedsson5

Enterococcus durans is a gram + cocci that is infrequently associated with diarrhea in humans, foals, piglets, puppies, calves, and rats. The purpose of this study was to identify pathogens associated with foals affected with diarrhea during the first 10 days after foaling. The farm of interest is a thoroughbred breeding farm where up to 30% of the newborn foals by 10 days of age develop diarrhea. In previous years the clinically affected foals have had Clostridium perfringens as well as Clostridium difficle detected in their feces. Despite the use of prophylactic antimicrobials (metronidazole) and infectious control measures, this farm continued to experience increased number of foals with diarrhea. Fifty‐nine foals and mares were sampled (feces) for diagnosis of selected pathogens 3 and 10 days after foaling. Samples were submitted to the Hagyard Equine Medical Institute for diagnosis of the following pathogens by culture: Salmonella, E. Coli, Aeromonas, E. durans and C. perfringens. Samples were also submitted to IDEXX for real‐time PCR of Cryptosporidium, Clostridium perfringens enterotoxin, Lawsonia, rotavirus, coronavirus, Clostridium difficle Toxin A and B, Rhodococcus equi and Salmonella. Results revealed no clear pattern of selected pathogens associated with diarrhea in affected foals and non‐affected foals, except for E durans. Five of 7 foals with diarrhea and 0 of 51 foals without diarrhea were classified as culture positive to E durans. The frequency of C perfringens or C difficle pathogens was similar in foals affected or not affected with diarrhea.

We have gradually been gaining study results of environmental risk evaluations for chemical substances hazardous to our health like benzene and dioxin. There are, however, about 100,000 chemical substances in use over the world and about 50,000 in Japan alone. Each year, the industries develop hundreds of new chemical substances, and environmental risks of most chemical substances have not been clarified at this time.

Chemical substances with scientific evaluation of their chemical risks are only a part of them all. The Act on the Evaluation of Chemical Substances and Regulation of Their Manufacture, etc. sets the rules of risk evaluation before introducing products into the market if they contain chemical substances that may cause health hazards. Chemical substances with large risk evaluation have their production banned or their use limited by this law. The fact, however, is chemical substances subject to such restrictions make only a small part with those with clear health damages by past pollution or confirmed health damages to workers in the production fields.

For most chemical substances, even without clear damages caused, their sizes of risks are not clarified. Currently, chemical substances suspected to pose large health hazards include persistent organic pollutants like dioxin, polychlorinated biphenyl (PCB), and dichlorodiphenyltrichloroethane (DDT). These substances hardly deteriorate in the natural environment; thus, they are persistent, and once discharged in the environment, they travel and diffuse to a wide area over the globe. Further, they accumulate when living organs take them into their bodies and thus are highly hazardous to ecological systems. Countries of the world have agreed to cooperate in regulating their production, like with Stockholm Convention; however, tackling the problem of their risk management at the global level is one that we just started.

In CL-3 facilities, gloves act as barriers, protecting persons by reducing the risk of exposure to infectious materials. Moreover, because they were removed and replaced after each manipulation, they also prevent pathogen dissemination in case of hands contamination. The glove selected must conform to EN 374 European standard, and the “Microorganism” pictogram should be present certifying that the glove was conformed to at least a performance level 2 for the penetration test (BS EN ISO 374-1:2016, “Protective gloves against dangerous chemicals and microorganisms. Terminology and performance requirements for chemical risks”). They must also be CE marked for specific use with biological agents. A double gloving strategy is generally the rule since it allows for removal and replacement of the outer glove without exposing the bare skin. Moreover, gloves should be the last piece of PPE to be donned; they must pull over the wrists of the gown. Nitrile gloves are preferred to latex gloves because they can provide better microbiological protection, as well as better protection against chemicals. However, under certain circumstances, powder-free latex gloves could be the better choice (when high degree of sensitivity and dexterity are required) (23).

These processes will add cost

Routine implementation in high‐income countries where endemic disease and exposure are rare is likely to continue to be debated on the basis of cost and benefit. Advances in adoption are likely to result when these processes can serve low‐income nations with significant blood safety concerns with affordable products made with high quality and low cost. Questions about implementation with patients who are most vulnerable and thus may benefit the most from these methods need to be asked. Such groups may include those receiving chronic transfusion support or pediatric patients where cost–benefit and risk–benefit calculations are likely to have their most favorable outcomes.143 Providing products to regions with high endemic disease rates can greatly improve cost–benefit analyses but will require partnerships with nongovernmental organizations and longer‐term considerations of sustainability in these environments when supplementation of costs is no longer feasible.144

We estimated the economic impacts of NIS on agricultural systems in Southeast Asia by combining information on the yield losses and the proportion of NIS in major pest groups. For example, in Southeast Asia, up to 46% of cassava production is lost to weeds, 22% of maize production to insects, and 22% of potato production to pathogens, (Table S1 in File S1 contains the proportions of yield losses in major crops by pest group and proportion of NIS in each pest group). Approximately 44% and 15% of the important weeds and arthropod pests, respectively, in Southeast Asia are of non-native origin. In each pest group, non-native species are not only high in number but also rated among the most damaging. Some examples includes the diamondback moth (Plutella xylostella) in Malaysia, the haganoy weed (Chromolaena odorata) in the Philippines, coffee rust (caused by the fungus Hemileia vastatrix) that led to the abandonment of coffee plantations in the region and ufra disease (caused by the nematode Ditylenchus angutus) that is one of the most important rice pathogens in Vietnam.

Losses from weeds, insects and pathogens were estimated as follows:(1)where YLi represent the economic value of the yield losses in crop i; ylweeds, ylinsects, ylpathogens are the proportions of yield losses caused by weeds, insects, and pathogens respectively; θNISweeds, θNISinsects

, θNISpathogens are the proportions of non-indigenous weeds, insect pests, and pathogens respectively; and Wi is the annual production value of crop i in Southeast Asia averaged over the period of 2000–2010.

We applied this estimation method to a database of 101 agricultural commodities produced in Southeast Asia including food crops such as cereals (e.g. maize, rice, wheat), vegetables (e.g. pea, spinach), fruits (e.g. mango, orange, coconut) and non-food crops (e.g. rubber, cotton). The information on yield losses and the proportion of those losses that are caused by each type of NIS were only available for some crops (see File S1). For example, out of the 101 considered, yield losses by weeds were known for only 12 major crops (e.g., oil palm, rice, rubber). Therefore we could only estimate yield losses directly in 49% of the total production value of crops affected by weeds and 44% of the crops affected by insect pests. For the remaining crops, we extrapolated by constructing uncertainty distributions using the Project Evaluation and Review Techniques (PERT) distribution with the information available from the crops in each pest group (parameterized using the minimum, median (as most likely value) and maximum proportion of yield loss and proportion of NIS respectively). PERT distributions are a version of the Beta distribution that requires the same parameters as the triangular distribution. It was preferred to the triangular distribution as it does not suffer the same systematic bias problems. We could not find information on the proportion of pathogens that are NIS, so we used the proportion of non-native insects as a proxy. Our assumption is based on the strong association between pathogens and their insect vectors.

We estimated the annual total losses to crop production by non-native weeds, insects, and pathogens to be $21.6 billion (5th to 95th percentile: $18.06–23.05 billion). Control costs associated with weeds, insects, and pathogens were, because of data paucity, only estimated for Malaysia, Myanmar and Thailand and could not be included for the remaining countries. We calculated these phytosanitary costs (phyCi) as follows:(2)where Uherb, Uins and Ufung&bac are respectively the usage of herbicides, insecticides, fungicides and bactericides; pherb, pins and pfung&bac represent respectively probability distributions of the prices of these chemicals, and ϑ

NISweeds, ϑ

NISinsects and ϑ

NISpathogens are the proportions of weeds, insects and pathogens that are NIS. Phytosanitary costs also include the control of pests in urban areas and golf courses.

We calculated pesticide usage by averaging annual usage data in these three countries from 2006 to 2008. Next, we estimated the cost caused by each pesticide group by constructing PERT uncertainty distributions using the annual suppliers’ price for the phytosanitary products in the Philippines as a surrogate. Our estimate of the annual pesticide costs imposed by exotic weeds, insects and pathogens in the three countries for which data were available amount to $3.5 billion (5th and 95th percentile: $2.62–4.58 billion).

The order of July 16, 2007 describes the minimal biosafety measures required for working with RG3 infectious pathogens in French academic laboratories. It sets out the minimal technical preventive measures to be implemented in laboratories conducting research, teaching, analysis, pathological anatomy, and cytology, in autopsy rooms, and in industrial and agricultural facilities. The French pathogen classification and a risk assessment define the required CL for working with infectious agents. However, for pathogens without natural aerosol infection and after a risk assessment, the article 4 states specific situations where RG3 agents can be down classified (working with an attenuated or a vaccine strain, low agent concentration, non-dangerous parasite stage, etc.). For biological samples potentially contaminated by a RG4 virus and in the case of urgent biomedical analysis, the article 5 allows us to perform molecular diagnosis on human samples in a CL-3 academic laboratory. Only, molecular diagnostic can be performed in CL-3, excluding virus isolation and propagation that can only be done in a CL-4 laboratory. Article 5 was enforced during the recent West African Ebola virus outbreak (order of August 6, 2014).

Although its costs in Southeast Asia could not be quantified, measles, probably of Middle Eastern origin, was the cause of nearly 10,500 deaths in Southeast Asia (excluding Brunei and Singapore) in 2008 alone. Malaria in Southeast Asia is mostly caused by two species of Plasmodium (P. falciparum and P. vivax), both of which are likely to be NIS,. Annual control costs of malaria for eight countries in Southeast Asia (excluding Brunei and Singapore) averaged for 2000–2011, to $92.8 million. A new epidemic of cholera could impose a heavy burden on vaccination and treatment in Southeast Asia. The cost to fully vaccinate a person is estimated at $1.10 in Vietnam while the cost of illness per episode of cholera in North Jakarta is $205.7 for hospitalized cases and $28.10 for outpatient cases. However, estimating the total burden of cholera in Southeast Asia was not possible because this disease is highly underreported. It is estimated that only 1% of cholera cases are reported, resulting in only 1,009 cases reported to WHO from Southeast Asia in 2012.

Quinoline is known for its bactericidal, antiseptic and antipyretic action. Chloroquine (CQ) belongs the quinoline group. It is a white or slightly yellow crystalline powder with bitter taste. It is a lysosomotropic weak base, soluble in water at pH 4.5 with molecular formula of C18H26CIN3. The derivatives of CQ includes chloroquine diphosphate (C18H29ClN3.2H3PO4), chloroquine phosphate (C18H29ClN3.H3PO4), chloroquine sulfate (C18H26ClN3. H2SO4) and chloroquine dihydrochloride (C18H26ClN3.2HCl). CQ has been used as a primary antimalarial drug since 1930s due to its tolerability, effectiveness against malaria and inexpensive synthesis. In addition to serving as a malarial drug, CQ is now used in cancer therapy due to its enhancement property against tumour activity. CQ is also shown to significantly improve insulin levels in type 2 diabetes (T2D). In addition CQ is used as an antifungal, it is used in the treatment of rheumatic and immune-mediated diseases, management of HIV, SARS-CoV and influenza A/H5N1 virus.

Unfortunately, CQ use could have various side effects in mammals such as cardiac arrest, blindness, arrhythmias, hypokalemia, retinopathy, renal failure and cerebral oedema. In addition, CQ treatment during pregnancy is extremely toxic to embryo and overdose could lead to death. The negative effect of CQ is due to the fact that it inhibits diastolic depolarization, which slows down conduction and alters the intracellular transport of ionic transport. It also inhibits glucose 6-phosphate dehydrogenase activity, enzyme synthesis in nucleic acids; cyclic AMP pathway and it also increase oxidative stress in the organs,. Due to its high affinity towards nucleates and nucleoproteins, CQ could accumulate in lysosomes, adrenal glands and in epithelial cells of kidney which alters the secretion of aldosterone.

Over production and extensive use of pharmaceuticals including CQ may reach the aquatic ecosystem mainly through sewage effluents, washing out of faecal materials by rain, domestic wastewater and STPs. The presence of these pharmaceutical drugs or their residues in the aquatic environment is a serious issue throughout the world. Due to their resistance to degradation and lipophilic property they persist in the aquatic environment and could have negative effects on the biota. So far, more than 100 pharmaceuticals have been identified the aquatic ecosystem, recently Ramaswamy et al. and Shanmugam et al. have detected pharmaceutical and personal care products such as carbamazepine, triclosan, parabens, diclofenac, ketoprofen, naproxen, ibuprofen and acetylsalicylic acid in Indian major rivers such as Kaveri, Vellar and Thamiraparani.

Ecological risks by manmade chemicals are a potential subject of concern. Toxicity of any chemical can be determined by using bioassay methods. Specifically fish bioassay is considered as crucial in the field of eco-toxicology. As fish are one of the most organisms of the aquatic food web, and as they are a chief sources of food all over the world and as they are highly sensitive to slight environmental changes, it is important to conduct fish bioassay. Bioassays play an important role in providing information about the impact of emerging chemicals. In addition to bioassay, biomarkers are considered as early warning signals in the field of environment risk assessment. The biomarker response reveals the health status of an organism, population and ecosystem. Biochemical and histological biomarkers are known to be sensitive tools to detect direct effects of pollutants in the specific organ. These biomarkers may provide information from the starting point of biological effects to the impact on cell physiology.

Among the biochemical biomarkers enzymes are commonly used as a marker of pathological alterations of the organ, as they rapidly respond to chemicals. Glutamate oxaloacetate transaminase (GOT or AST), glutamate pyruvate transaminase (GPT or ALT) and lactate dehydrogenase (LDH) are the enzymes found in heart, liver, kidney, skeletal muscles and erythrocytes. GOT and GPT participate in transamination reactions. Likewise, LDH is an oxidative enzyme which is important for glycolytic activity. The alterations in these enzymes are used as organ health indicators of chemical exposure. GOT, GPT and LDH are widely used enzymological parameters in toxicology and in clinical chemistry to know the status of organs. Similarly, histopathological changes provide the direct effects of the toxicant in organs and also reveal the difference between damage induced by toxicant and other factors in organs/tissues. In fish, gills are the primary site of toxicant exposure and their structural changes indicate the impact of toxicant. Liver is the second largest organ in the body and are known to be a defense organ. Antoine et al. reported that liver is the major target area of human pharmaceuticals. Likewise kidney is a target organ for many pharmaceutical drugs. Hence, histological observation of vital organs such as gill, liver and kidney are important biomarkers in determining the toxic effect of human pharmaceuticals.

The present study was carried out to evaluate the acute and sublethal toxicity of chloroquine (CQ), an antimalarial drug in a freshwater fish Cyprinus carpio using certain biomarkers. The experimental model C. carpio is a common carp cultured widely in India

Cassiae semen, also known as ‘Juemingzi’ in Chinese, is the dry and mature seed of Cassia obtusifolia L. or C. tora L., which belong to the Cassia genus of Leguminosae (1). It is cultivated in Korea, Japan and China, and is commonly consumed as a roasted tea (2,3). In traditional Chinese medicine, it has been used in treatments for hyperlipemia, diabetes mellitus, Alzheimer's disease, acute liver injury, inflammation, photophobia, headache, dizziness and hypertension (4–6).

Phytochemical investigations have isolated and identified >70 compounds, including anthraquinones, naphthopyrones, volatile oils and sterols (7,8). Among these, anthraquinones are the primary functional components and possess a wide spectrum of pharmacological properties (9–11), including antihyperlipidemic, neuroprotective, hepatoprotective, antibacterial and antimutagenic activities (12–14). Naphthopyrones, other primary components, exhibit antidiabetic (15,16), antimicrobial (17), antiestrogenic (18), antiallergic (19) and anthelmintic effects (20). At present, the Pharmacopoeia of the People's Republic of China recommends the use of chrysophanol and aurantio-obtusin as the indicator components, and the quality of Cassiae semen is evaluated primarily by assessing the content of these two compounds (1).

The purpose of the present review is to provide comprehensive information on the ethnobotany, phytochemistry and pharmacology of Cassiae semen collated from previous studies, in order to facilitate the further study and application of Cassiae semen, as well as generate a novel basis for the associations between structure and activity, and their molecular mechanisms of action.

In conclusion, this review therefore addresses two main aspects, both the emerging drug repurposing strategy and resistance to last-line antibiotics, carbapenems, and colistin. A new economic model is to be considered for antibiotic development because industries do not seem interested in this new strategy (Zheng et al., 2018). Indeed, as antibiotics are not part of chronic treatment strategies, this could not be as economically attractive (Conly and Johnston, 2005). This disinterest in antibiotics research is reflected in their absence in programs of future developments of major pharmaceutical companies (Spellberg et al., 2004). Start-ups or small companies, on the other hand, can see an interest in taking back antibiotics that have failed in clinical phases, for example. They believe they have different drug development strategies and do not require as many benefits to cover their costs compared to multinational pharmaceutical companies (Fernandes and Martens, 2017). However, Phase 3 clinical trials for new and repurposed drugs remain very expensive: it is estimated between $40 million and $300 million of USD (Azvolinsky, 2017). With such a budget, this does not work in favor of small firms.

As for the question of how to treat bacterial resistance, only one answer has not been found and the future offers us new possibilities. Various strategies are being considered as treatment using fecal microbiota (Davido et al., 2017), antimicrobial peptides (Hashemi et al., 2017) or bacteriophages (Parmar et al., 2017). A Streptomyces sp. present in alkaline soil in Ireland has been in the spotlight recently to inhibit growth of MDR bacteria (Terra et al., 2018) which reminds of Flemming discovery. Additionally, the discovery and studies on the CRISPR/Case9 system may suggest that it may be the ultimate weapon to fight infectious diseases and thus control antibiotic resistance (Doerflinger et al., 2017).

Question of drug repurposing remains rather wide. Although this seems to be a better solution, drug combinations can also lead to adverse interactions. First, toxic side effects can be increased. Then, concerning compound galenic, physico-chemical interactions and differences in stability, solubility and conservation can result from the combination of two molecules making it incompatible. Formulation then becomes more complicated (Sun et al., 2016a). On the other hand, we must change this vision where each drug belongs to only one box. Clinicians may have difficulty understanding why a biologist recommends the use of an anti-cancer or anti-inflammatory drug to treat their cystic fibrosis patient's bacteremia rather than a last resort antibiotic they have always used. Communication in this sense remains essential between health professionals and clinical studies to prove these activities are critical. However, with current knowledge on drug repurposing as antibacterial agents and the problematic to find an alternative therapeutic in some situations, screening of non-antibiotics in a “à la carte” way can be an issue (Figure 4). In the area of personalized medicine, we could imagine a personalized antibiotic susceptibility testing in case of infection caused by a highly resistant bacterium. If all last-line antibiotics have been tested and appear insufficient to successfully treat the patient, testing non-antibiotic drugs that are potentially active on the pathogen, alone or in combination with antibiotics, could help clinicians use these drugs. As previously reported by Kadri et al., these difficult-to-threat bacteria refer to bacteria that are resistant to all first-line antibiotics. It represents less than 1% of isolates and those that are resistant to second-line antibiotics are even rare (Kadri et al., 2018). This solution, combined with monitoring of serum levels and adverse events such as dialysis of a nephrotoxic drug (Rolain and Baquero, 2016), could offer great potential for treating a patient with this MDR bacterium. The problem remains to be able to routinely test a large panel of molecules, in an automated, reproducible, and not too expensive way.

Nowadays, despite recent scientific progress, infectious diseases must always be taken into consideration. The World Health Organization (WHO) closely examines such concerns in order to have an effective health system (World Health Organization, 2018). For 50 years, we have been confronted with the end of the golden age of antibiotic discovery, while some antimicrobial substances have existed for years (Gould, 2016). Due to significant progress that has largely contributed to reducing the number of deaths from infectious diseases, pharmaceutical companies have developed a decreasing interest in these drugs (Conly and Johnston, 2005).

In addition, the use of an antibiotic and the emergence of its resistance are inevitable and intrinsically linked (Mohr, 2016). Although this is not a new phenomenon but a natural one, WHO analysis warns against this serious situation which is the impact, nature and spread of global antimicrobial resistance (Global Antimicrobial Resistance Surveillance System, 2019 Report Early implementation). These resistant bacteria are found in every kind of environment: water, animals, humans, plants and food (Rolain, 2013; Zenati et al., 2016; Bachiri et al., 2017; Tafoukt et al., 2017). The inappropriate use of antimicrobial agents and the spread of antibacterial resistance are among factors that lead to a high rate of resistance in clinical, animals, and even in environmental isolates (Roca et al., 2015; Bassetti et al., 2017). Partly because of drug pressure, resistance can occur more easily and affect all types of antibiotics as for the last-line antibiotics used in human medicine drug for resistant bacterial infections (Biswas et al., 2012). In recent years, we have seen an increase in the use of carbapenems as a result of an increase in the carbapenem resistance of Gram-negative bacteria (GNB) (Diene and Rolain, 2013). For example, Monaco et al. showed in Italy that among 191 clinical strains isolated from November 2013 to April 2014, 178 (93%) Klebsiella pneumoniae had KPC enzymes (carbapenemases), with 76 (43%) resistant to colistin (Monaco et al., 2014). Although the same situation has been reported with colistin (Olaitan et al., 2014), it has received more attention: last-line treatments may no longer be effective, increasing the risk of spreading infections (Biswas et al., 2012). To combat frequent epidemics and the challenge of rapid spread, new alternatives to last resort treatments must be considered to avoid treatment failure.

As a result, alternatives to antibiotics to treat resistant germs should be a priority (Bassetti et al., 2017). The use of old drugs can be a solution like “forgotten” antibiotics polymyxins, fosfomycin, minocycline or mecillinam, which are still used in clinical settings (Cassir et al., 2014). There is also a renewed interest in antibiotic combinations to circumvent resistance (Lenhard et al., 2016). For example, the synergistic activity of sulfonamide-associated colistin was evaluated against colistin-resistant clinical bacteria (Okdah et al., 2018). But “non antibiotic” solutions can also been considered as alternatives for the therapeutic management of infections (Aslam et al., 2018). Various studies showed that Clostridium difficile can be inhibited using bacteriophages or several ongoing trials use antimicrobial peptides as alternatives or preventive treatments in the future (Aslam et al., 2018).

The fight to treat multi-drug resistant (MDR) infections must also include a change in mentality. Rolain and Baquero denounced the fact that society does not accept the use of toxic but effective antibiotics in treatment of life-threatening infections, but on the other hand society can tolerate potential toxicities of other drugs, such as anti-cancer. With the progress of medicine in the management of adverse reactions and the improved monitoring of antibiotic concentrations, old drugs or dosages rejected due to their adverse effects have to be reconsidered (Rolain and Baquero, 2016). In this way, one other promising alternative on which this review focuses is drug repurposing, also called repositioning (Mercorelli et al., 2018). This therapeutic shift is the subject of several studies in different pathologies including cancer (Sleire et al., 2017), heart diseases (Sun et al., 2018), Alzheimer's disease (Kim, 2015) or depression (Ebada, 2017).

In infectiology, repurposing studies are now being carried out (Torres et al., 2016; Soo et al., 2017; D'Angelo et al., 2018; Zheng et al., 2018; Miró-Canturri et al., 2019). In general, the most common bacteria are first tested or those most at risk or in a therapeutic deadlock. If this review focuses on drug repurposing that have been tested on MDR bacteria, it seems important to precise that resistance is rarely crossed and if a molecule is active on a specific species, this compound will potentially be active regardless of its resistance mechanisms. This is because this molecule affects a new target, generally independent of the antibiotic target, as we will see below with ciclopirox (Carlson-Banning et al., 2013), gallium (Goss et al., 2018), and zidovudine (Elwell et al., 1987). Therefore, it can expand the scope to combinations tested on sensitive GNB as for minocycline and polymyxin B tested with non-antibiotics drugs (Schneider et al., 2017). It offers a diversified and still exploitable field of possibilities (Schneider et al., 2017). For carbapenem and colistin-resistant isolates, a few articles are published on this specificity for which we are striving to synthesize them. The aim is thus to identify an innovative therapeutic strategy against these bacteria in a cost-effective and efficient way.

In this review, we will define drug repurposing and its characteristics. We will then make an inventory of what has already been published as a drug for reuse in general and in particular to address the problem of carbapenem and colistin-resistant bacteria. Finally, we will see what prospects exist for this therapeutic strategy.

In summary, based on the literature report and our previous work, a series of phenanthroquinolizidine alkaloids 1–24 were designed, prepared and evaluated for their anti-TMV activity for the first time. The in vitro and in vivo antiviral bioassays showed that most of these alkaloids exhibited good to excellent in vivo anti-TMV activity, of which compounds 1, 2, 15 and 16 displayed significantly higher activity than (R)-antofine and commercial Ningnanmycin at the same test condition. The in vitro activity and in

vivo activity of each alkaloid are about similar, which indicates that these alkaloids possess a good biological availability. The introduction of 6-hydroxyl, which is proposed to interact with TMV RNA, did increased anti-TMV activity. The 14aR-configuration was confirmed to be the preferred antiviral configuration for phenanthroquinolizidine alkaloids. Introduction of hydroxy group at 15-position of phenanthroquinolizidine alkaloids increased antiviral activity for S-configuration but decreased activity for R-configuration. Present study provides fundamental support for development and optimization of phenanthroquinolizidine alkaloids as potential inhibitors of plant virus. To the best of our knowledge, this is the first report on anti-TMV activity of phenanthroquinolizidine alkaloids. Further studies on mode of action are currently underway in our laboratories.

Nanotechnology is an important emerging industry with a projected annual market of around one trillion US dollars by 2015. It creates novel materials with a variety of useful functions, including many that could be exceptionally beneficial in medicine. However, concerns are growing that it may have toxic effects, particularly damage to the lungs. The application of nanotechnology in medicine need special attentions is required related to the toxicology of nanoparticles and nanostructures. Therefore, exclusive nanotoxicology studies are warranted, particularly the subcategory of toxicology. Classical categories are required for toxicological risk assessment of the use of nanoparticles, including hazard identification, hazard characterization, exposure assessment, and risk calculation Luther (2004). Since there are practically no toxicology studies available on the emerging applications of nanotechnology in medical technology, therefore studies are urgently required to address toxicological risks of the application of nanotechnology in medical technology. Furthermore, there is a lack of knowledge on the fate of ingested nanoparticles in human body and it is essential to investigate routes of exposure and also it is important to know about basic knowledge of their absorption, distribution, metabolism, and excretion. Finally, the implementation of a risk management strategy is required for all medical products using nanoparticles for all medical technology applications.

There will be a measurable reduction in cell or protein quality after treatment

Preclinical studies and clinical trials with PRTs conducted in the preceding 18 years have repeatedly demonstrated changes in both in vitro and in vivo variables.129 These include changes in metabolic variables in treated PLTs, changes in aggregation, and adhesion function and changes in PLT proteomic and metabolomics measurements.130 Similar results with plasma products have shown reduced coagulation factor levels after treatment.131 Clinical studies evaluating the performance of these products have demonstrated noninferiority with regard to prevention of bleeding in patients with hematologic malignancies. Estcourt and colleagues, summarizing meta‐analyses for 12 clinical trials with these products, indicated that “We found moderate‐quality evidence that pathogen‐reduced platelet transfusions do not affect all‐cause mortality, the risk of clinically significant or severe bleeding, or the risk of a serious adverse event.”132, 133 The authors also noted that, “We found high‐quality evidence that pathogen‐reduced platelet transfusions increase the risk of platelet refractoriness and the platelet transfusion requirement.”132, 133

When compared to control group plasma GOT activity significantly (F4,24 = 1.522***) increased at the end of 7 and 14th days of exposure (Fig. 2). However after 21, 28 and 35th day of exposure GOT activity decreased significantly (F4,24 = 1.522***) in CQ treated groups when compare to control group.

An annual loss of 2.1 million DALYs in EU-26 is associated to indoor and outdoor originating pollutants with more than half of it (1.28 million DALYs) caused by exposures to outdoor air pollution indoors and the remaining 0.74 million DALYs caused by indoor source pollutants.

This burden of disease is dominated by cardiovascular (CV) diseases as a result of exposure to outdoor and indoor particles and second hand smoke, corresponding 57 % of the total burden of disease (Fig. 1). The second largest contribution comes from lung cancer (23 %) and the third in the list is asthma (total of 12 %). The remaining 8 % is divided between various respiratory symptoms and conditions.

The total burden of disease for individual countries varies considerably with the highest burden of 10 000 DALY per one million population in Bulgaria to the lowest one of 2 000 DALY per million in Sweden. The EU-26 average burden of disease is slightly over 4 000 DALY in a year per one million population. The higher levels in East-European countries are dominated by high contribution of outdoor sources, which vary from 46 % (Ireland) to 75 % (Bulgaria) (Fig. 2).

Influenza is responsible for substantial morbidity and mortality worldwide [1–5]. Globally, influenza is estimated to adversely affect up to 5% to 10% of adults and 20% to 30% of children each year. Annual influenza epidemics in the United States result in nearly 600,000 life-years lost, 3.1 million days of hospitalization, and 31.4 million outpatient visits; in addition, the total economic burden of influenza exceeds $80 billion. Current prevention strategies for influenza are dependent on the use of anti-influenza medications and vaccines.

Neuraminidase inhibitors (NAIs, eg oseltamivir) are approved in the United States to prevent and treat influenza [8, 9]. However, the use of antiviral medications for pre-exposure prophylaxis has a very limited role and is generally not recommended for the majority of the population. Also, NAIs confer only modest decreases in symptom duration for individuals presenting with uncomplicated illness [11–13], and this treatment suffers from the selection of resistant strains, adverse effects, and high cost [14–16]. While the most effective way to prevent influenza disease and its severe outcomes is by vaccination, current coverage estimates are well below the Healthy People 2020 goal of 70% [17, 18]. Additionally, vaccine/strain mismatch can result in low vaccine efficacy [19–22]. Vaccines may also be contraindicated, unavailable, less effective in immuno-compromised individuals, and suffer from perceived risks leading to “vaccine hesitancy” [23, 24]. Therefore, the development of effective novel strategies to prevent and treat influenza disease is a significant unmet need.

Cetylpyridinium chloride (CPC) has been used for decades against a variety of pathogens [25–28], and it disrupts the microbial lipid bilayer through physicochemical interactions, a mechanism that is unlikely to be affected by mutations in addition to being pathogen independent. For this reason, CPC and other quaternary ammonium compounds are commonly employed in the prevention of bacterial and fungal infections within healthcare settings. Yet there is little evidence demonstrating their effectiveness against respiratory viruses. Here, we evaluated CPC efficacy against the prototypical respiratory influenza virus demonstrating: (1) direct virucidal activity against influenza, (2) rapid activity following exposure, (3) viral ultrastructure disruption, (4) absence of influenza resistance following prolonged exposure, and (5) prevention and treatment of influenza infection in a murine model.

The metal oxide nanoparticles, particularly Zinc oxide nanoparticles are most commonly used in catalysis, sensors, and environmental remediation and personal care products. Recently, ZnO-NPs that were used in various applications of veterinary sciences due to their antibacterial, antineoplastic, wound healing, and angiogenic properties, and further ZnO-NPs have been used in tissue repair, as food preservative and as feed additive. ZnO-NPs found to inhibits the viability wide range of bacteria by strong interaction with bacterial cells and it could induce microbial cell injury by the generation of hydrogen peroxide from the surface of ZnO and finally it can enter into the bacteria by interacting with phosphorus and sulphur containing compounds, like DNA of bacteria. Mastitis is a disease of high yielding animals that is commonly caused by Staphylococcus, Streptococcus, and E. coli, which leads to economic consequences by reducing the yield of milk. To treat various causative agents of mastitis the usage of antibiotics has been increased and eventually leads to antibiotic resistance. ZnO-NPs have been found to be effective against biofilm inside the udder tissue causative agents, such as S. aureus and E. coli. Arabi et al. found that the bactericidal effects on both Gram-positive and Gram-negative bacteria and also effective against spores that are resistant to high temperature and high pressure by the mechanism of increase the permeability and inhibition of membrane transport and eventually leads to cell death. To determine the effect of Zinc oxide nanoparticles on various mastitis causing bacteria, including Staphylococcus epidermis, Streptococcus agalactiae, Klebsiella pneumoniae, and E. coli, the prepared ZnO-NPs with an average size of 20 nm (Figure 6). While the pathogenic bacteria treated with ZnO-NPs shows that pronounced decreased level of cell viability in all the tested bacterial strains (Figure 7).

The peculiar properties of ZnO NPs such as selective toxicity of preferential killing of cancer cells with minimal toxicity to normal primary immune cells and cancer cells, it can be used anti-cancer agent in both humans and veterinary animals, and also it is more sensitive to detect cancer biomarkers, therefore it can be easily used in ZnO-NPs based diagnostic devices. Due to all these, salient features of ZnO-NPs leads to significant usage in diagnostic and therapeutic purposes in common neoplastic conditions of animals, like lymphoma, cutaneous cancer, transmissible veneral tumor, and equine sarcoids. Recently, neoplastic disorder was most frequently found in in domestic animals, for example, haematopoietic tumours, canine transmissible veneral tumor in canines, and equine sarcoid is the most common fibroblastic skin tumor affecting horses, mules, and donkeys. These neoplastic conditions could be treated by ZnO NPs. Zinc oxide was used as feed additive in weaner piglets to overcome the effect of post-weaning diarrhoea (PWD) caused by enterotoxigenic E. coli, which causes an increase in morbidity and mortality and decrease growth rate during the weaning period in piglets. Similarly, the addition of zinc (zinc oxide) at the concentration of 2500 to 3500 ppm in feed modulated the microbial status of the digestive tract and reduced the incidence of post-weaning diarrhoea in piglets and increased productive performances. Zn is mainly used in human and livestock foods and feeds for normal physiological functions, as well as to meet the daily requirement. Salama et al. studied the effects of dietary supplements of zinc-methionine on milk production, udder health and zinc metabolism in dairy goat, the results showed that addition of Zn enhanced resistance to udder stress in dairy goats to Zn supplementation. When supplemented to poultry leads to increase the level of ADFI, ADG, DM, and intramuscular fat contents of the breast muscle, percentage of eviscerated yield, redness value in breast muscle, and pH values in thigh muscle and decreased shear force in thigh muscle, drip loss in breast and thigh muscle. ZnO-NPs enhanced growth performance, improve feed utility and provide economic benefits in weaning piglets and growth, production, and dress performance in poultry. The supplementation of increased doses of Zn up to 3000 mg/kg increases the growth and reduces diarrhoea in pigs. Rajendran et al. found that the application of Nano Zn reduced the level of the somatic cell counts in cows with subclinical mastitis and improve milk production when compared with other conventional ZnO sources. Zn deficient diets are a cause of high incidence of abortions and stillbirths and supplementation in the form of Zn nanoparticle to animals increase the reproduction.

The beneficial effects and toxic effects of any nanomaterials depend on size, shape, surface charge, dose response, aggregation, type of solvent, and type of host cells. ZnO-NPs not only causes beneficial effects but also causes the toxicity effect in several veterinary animals. ZnO-NPs causes severe toxicity in the pancreas; kidney, liver, rumen, abomasum, small intestine, and adrenal gland were observed in sheep. Liver, spleen, heart, pancreas, and bone are the target organs of ZnO-NPs on oral exposure. Najafzadeh et al. observed the mild liver toxicity and severe renal damage in lambs.

It is well established that many microbes are associated with or are colonizing on natural cordyceps. Except for the 22 fungal species reported to be associated with natural Chinese cordyceps during the 1980s and 1990s (Jiang and Yao 2002), mycoflora investigation indicated the richness of fungal diversity on Chinese cordyceps based on culture-dependent and culture-independent methods (Zhang et al. 2010). Many new novel secondary metabolites have been identified from the cordyceps-colonizing fungi (Zhang et al. 2007, 2009; Guo et al. 2007; Guo, Sun, Gao, Chen, et al. 2009; Guo, Sun, Gao, Niu, et al. 2009; Ma et al. 2011). There is no doubt that the cordyceps-colonizing fungi are important resources for the discovery of novel compounds and for developing medicinal and healthy products. A coordinated effort between the industry and the scientific research community is needed to advance the whole cordyceps industry.

In traditional Chinese herbal medicine, Cassiae semen is used for the prevention and treatment of hyperlipidemia. Several Chinese herbal formulations containing Cassiae semen is available in the Chinese market for preventing the formation of atherosclerotic plaques (59). In certain Asian countries, including China and Korea, it is also commonly drunk as a roasted tea to reduce body weight (60,61). Previous studies using mice have evaluated the reductions in blood lipid contents induced by different Cassiae semen extracts obtained through different methods, including supercritical fluid extraction, systematic solvents (petroleum ether, ethyl acetate, n-butanol, 70% ethanol and water) and ethanol precipitation following water extraction. The results revealed that the n-butanol and ethyl acetate extracts were the most effective (62,63). In addition, the ethanol and aqueous extracts of Cassiae emen significantly decreased the serum levels of total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C), however, they increased the levels of high-density lipoprotein cholesterol (HDL-C) (13,64,65). Similarly, He et al (66) reported that treatment with the water extract form of C. obtusifolia seeds decreased the blood-lipid level by inhibiting cholesterol synthesis. Cho et al (67) demonstrated that soluble fibers from C. tora seeds markedly decreased liver TC and TG levels in rats fed with a high-cholesterol diet. The underlying mechanism may be mediated by increasing fecal bile acid excretion and downregulating the production of lipogenic enzymes (67). In addition, soluble fibers decreased the serum levels of TC, TG and LDL-C in patients with type II diabetes without serious adverse effects (2). Liu et al (68) revealed that the ethanol extract of Cassiae semen upregulated the expression levels of peroxisome proliferator-activated receptor (PPAR)-γ, sterol regulatory element-binding protein-1c, hormone-sensitive lipase and triacylglycerol hydrolase, however, tumor necrosis factor receptor superfamily member 6 was downregulated in adipose tissue. The anti-hyperlipidemia activity of Cassiae semen is primarily due to its antioxidant components, such as anthraquinones and polysaccharides. There are a variety of bioactive anthraquinone components in Cassiae semen, including chrysophanol, physcion, aurantio-obtusin, obtusifolin and emodin, which have been observed to decrease the levels of TC and TG (69,70). Previous studies have demonstrated that anthraquinones isolated from Cassiae semen were effective substances during hypolipidemic activities (71,72). These results were verified by a previous study, which applied an experimental hyperlipidemic rat model to investigate anthraquinone treatment (80 and 20 mg/kg, per os, for 20 days). The TC, TG and LDL-C levels were significantly reduced in a dose-dependent manner, however, the levels of HDL-C increased. Inhibition of cholesterol synthesis may be one of the underlying mechanisms involved in decreasing blood lipid levels (73). Water-soluble polysaccharides (WSPs) from Cassiae semen markedly inhibited the activities of α-amylase and pancreatic lipase, however, protease activity increased. The results demonstrated that WSPs had the ability to bind to bile acids and reduce the absorption of cholesterol, indicating that WSPs may have potential as an effective herbal ingredient in functional food applications (74).

COPD is not only associated with smoking, but also has high incidence among non-smokers. The risk factors for COPD among non-smokers include indoor air pollution from biomass combustion and second-hand tobacco smoke, as well as occupational exposures and outdoor air pollution [32–34]. Epidemiological studies from both developing and developed countries have shown the association between outdoor PM exposure and COPD. In addition to PM, ozone and NO2 could also exacerbate COPD. An increase in ambient PM2.5 could induce acute exacerbations and mortality from COPD, while improvement in air quality decreases the incidence of COPD [32–34].