The role of the European centre for the validation of alternative methods (ECVAM) in the validation of (Q)SARs

Under the current chemicals legislation, the regulatory use of structure-activity relationships (SARs) and quantitative structure-activity relationships (QSARs), collectively referred to as (Q)SARs, for the assessment of chemicals is limited, partly due to concerns about the extent to which (Q)SAR estimates can be relied upon. On 29 October 2003, the European Commission adopted a legislative proposal that foresees the introduction of a new regulatory system for chemicals called REACH (Registration, Evaluation, and Authorisation of Chemicals), which will impose equivalent information requirements on both new and existing chemicals. For reasons of practicality, cost-effectiveness and animal welfare, it is envisaged that (Q)SARs will play an important role in the assessment of some 30,000 existing chemicals for which further information may be required under the REACH system. It will therefore be essential that the (Q)SAR models used will produce reliable estimates. To overcome the barriers in the acceptance of (Q)SARs for regulatory purposes, it is widely acknowledged that there needs to be international agreement on the principles of (Q)SAR validation, and that the process of (Q)SAR validation should be managed by independent organisations, with a view to providing independent advice to the regulators who make decisions on the acceptability of (Q)SARs. The European Centre for the Validation of Alternative Methods (ECVAM), which is part of the European Commission's Joint Research Centre (JRC), has a well-established role in providing independent scientific and technical advice to European policy makers. This paper describes progress made at an international level regarding the principles of validation, and explains the role of ECVAM regarding the practical validation of (Q)SARs.     

Structure-based modelling in reproductive toxicology: (Q)SARs for the placental barrier

The replacement of animal testing for endpoints such as reproductive toxicity is a long-term goal. This study describes the possibilities of using simple (quantitative) structure-activity relationships ((Q)SARs) to predict whether a molecule may cross the placental membrane. The concept is straightforward, if a molecule is not able to cross the placental barrier, then it will not be a reproductive toxicant. Such a model could be placed at the start of any integrated testing strategy. To develop these models the literature was reviewed to obtain data relating to the transfer of molecules across the placenta. A reasonable number of data were obtained and are suitable for the modelling of the ability of a molecule to cross the placenta. Clearance or transfer indices data were sought due to their ability to eliminate inter-placental variation by standardising drug clearance to the reference compound antipyrine. Modelling of the permeability data indicates that (Q)SARs with reasonable statistical fit can be developed for the ability of molecules to cross the placental barrier membrane. Analysis of the models indicates that molecular size, hydrophobicity and hydrogen-bonding ability are molecular properties that may govern the ability of a molecule to cross the placental barrier.     

Structure-based modelling in reproductive toxicology: (Q)SARs for the placental barrier†

The replacement of animal testing for endpoints such as reproductive toxicity is a long-term goal. This study describes the possibilities of using simple (quantitative) structure-activity relationships ((Q)SARs) to predict whether a molecule may cross the placental membrane. The concept is straightforward, if a molecule is not able to cross the placental barrier, then it will not be a reproductive toxicant. Such a model could be placed at the start of any integrated testing strategy. To develop these models the literature was reviewed to obtain data relating to the transfer of molecules across the placenta. A reasonable number of data were obtained and are suitable for the modelling of the ability of a molecule to cross the placenta. Clearance or transfer indices data were sought due to their ability to eliminate inter-placental variation by standardising drug clearance to the reference compound antipyrine. Modelling of the permeability data indicates that (Q)SARs with reasonable statistical fit can be developed for the ability of molecules to cross the placental barrier membrane. Analysis of the models indicates that molecular size, hydrophobicity and hydrogen-bonding ability are molecular properties that may govern the ability of a molecule to cross the placental barrier.     

Chitosan nanoparticles: a promising system in novel drug delivery

The ability of nanoparticles to manipulate the molecules and their structures has revolutionized the conventional drug delivery system. The chitosan nanoparticles, because of their biodegradability, biocompatibility, better stability, low toxicity, simple and mild preparation methods, offer a valuable tool to novel drug delivery systems in the present scenario. Besides ionotropic gelation method, other methods such as microemulsion method, emulsification solvent diffusion method, polyelectrolyte complex method, emulsification cross-linking method, complex coacervation method and solvent evaporation method are also in use. The chitosan nanoparticles have also been reported to have key applications in parentral drug delivery, per-oral administration of drugs, in non-viral gene delivery, in vaccine delivery, in ocular drug delivery, in electrodeposition, in brain targeting drug delivery, in stability improvement, in mucosal drug delivery in controlled drug delivery of drugs, in tissue engineering and in the effective delivery of insulin. The present review describes origin and properties of chitosan and its nanoparticles along with the different methods of its preparation and the various areas of novel drug delivery where it has got its application.     

Orthogonal Cysteine Protection Enables Homogeneous Multi-Drug Antibody–Drug Conjugates

A strategy for the preparation of homogeneous antibody–drug conjugates (ADCs) containing multiple payloads has been developed. This approach utilizes sequential unmasking of cysteine residues with orthogonal protection to enable site-specific conjugation of each drug. In addition, because the approach utilizes conjugation to native antibody cysteine residues, it is widely applicable and enables high drug loading for improved ADC potency. To highlight the benefits of ADC dual drug delivery, this strategy was applied to the preparation of ADCs containing two classes of auristatin drug-linkers that have differing physiochemical properties and exert complementary anti-cancer activities. Dual-auristatin ADCs imparted activity in cell line and xenograft models that are refractory to ADCs comprised of the individual auristatin components. This work presents a facile method for construction of potent dual-drug ADCs and demonstrates how delivery of multiple cytotoxic warheads can lead to improved ADC activities. Lastly, we anticipate that the conditions utilized herein for orthogonal cysteine unmasking are not restricted to ADCs and can be broadly utilized for site-specific protein modification.     

The application of biomacromolecules to improve oral absorption by enhanced intestinal permeability: A mini-review

Oral administration has been widely regarded as the most convenient, quick and safe approach compared to other routes of drug delivery. However, oral absorption of drugs is often limited due to rigorous environments and complex obstacles in gastrointestinal tract. Having received considerable attention, biomacromolecules have been applied for oral drug delivery to improve the bioavailability, which could be attributed to its stability and unique bioactivities, including intestinal adhesion, opening of epithelial tight junctions, inhibiting cell efflux and regulating relative protein expression. Specifically, enhancing intestinal permeability has been regarded as a promising strategy for improving bioavailability of oral drug delivery. In this review, a series of biomacromolecules and the related mechanisms of increasing intestinal permeability for enhanced oral bioavailability are comprehensively classified and elucidated. In addition, recent advances in biomacromolecules based oral delivery and related future directions are mentioned and predicted in this review article.     

Orthogonal Cysteine Protection Enables Homogeneous Multi‐Drug Antibody–Drug Conjugates

A strategy for the preparation of homogeneous antibody–drug conjugates (ADCs) containing multiple payloads has been developed. This approach utilizes sequential unmasking of cysteine residues with orthogonal protection to enable site‐specific conjugation of each drug. In addition, because the approach utilizes conjugation to native antibody cysteine residues, it is widely applicable and enables high drug loading for improved ADC potency. To highlight the benefits of ADC dual drug delivery, this strategy was applied to the preparation of ADCs containing two classes of auristatin drug‐linkers that have differing physiochemical properties and exert complementary anti‐cancer activities. Dual‐auristatin ADCs imparted activity in cell line and xenograft models that are refractory to ADCs comprised of the individual auristatin components. This work presents a facile method for construction of potent dual‐drug ADCs and demonstrates how delivery of multiple cytotoxic warheads can lead to improved ADC activities. Lastly, we anticipate that the conditions utilized herein for orthogonal cysteine unmasking are not restricted to ADCs and can be broadly utilized for site‐specific protein modification.     

The role of crown ethers in drug delivery

The unique structure of the crown ethers has attracted the attention of many scientists to the use of these compounds in organic synthesis, and drug delivery. In recent years, extensive research has been conducted on the use of crown ethers in the drug delivery process. In the drug delivery process, the use of compounds that can act selectively is very important. Crown ethers with their unique structure can appear in various roles in drug delivery. In recent years, the use of crown ethers in the formulation of nano-drugs have attracted the attention of many researchers, and it shows that crown ethers have a great potential in the process of drug delivery. In fact, chemistry plays a role as a medium for transferring information from suitable compounds to drug delivery. Reviewing the results of the research provides the opportunity to create new ideas for using crown ether in new drug delivery systems.     

The Application of Structure-Activity Relationships (SARs) in the Aquatic Toxicity Evaluation of Discrete Organic Chemicals

Abstract

The Office of Pollution Prevention and Toxics (OPPT), United States Environmental Protection Agency (USEPA) routinely uses structure-activity relationships (SAR) for the aquatic hazard assessment of new chemicals submitted under Section 5 of the Toxic Substances Control Act (TSCA). With 15 years of experience and the general acceptance of toxicity predictions based on SARs, OPPT has expanded the use and application of the methodology to include existing chemicals used in printing, dry cleaning, and paint stripping. SAR analysis has also been used in the hazard evaluation of the U.S. and EU/OECD high production volume (HPV) chemicals. This paper describes the assumptions, limitations, and methodology for the use of SARs to evaluate large sets of discrete organic chemicals.     

Novel Antiretroviral Therapeutic Strategies for HIV

When the first cases of HIV infection appeared in the 1980s, AIDS was a deadly disease without any therapeutic alternatives. Currently, there is still no cure for most cases mainly due to the multiple tissues that act as a reservoir for this virus besides the high viral mutagenesis that leads to an antiretroviral drug resistance. Throughout the years, multiple drugs with specific mechanisms of action on distinct targets have been approved. In this review, the most recent phase III clinical studies and other research therapies as advanced antiretroviral nanodelivery systems will be here discussed. Although the combined antiretroviral therapy is effective in reducing viral loading to undetectable levels, it also presents some disadvantages, such as usual side effects, high frequency of administration, and the possibility of drug resistance. Therefore, several new drugs, delivery systems, and vaccines have been tested in pre-clinical and clinical trials. Regarding drug delivery, an attempt to change the route of administration of some conventional antiretrovirals has proven to be successful and surpassed some issues related to patient compliance. Nanotechnology has brought a new approach to overcoming certain obstacles of formulation design including drug solubility and biodistribution. Overall, the encapsulation of antiretroviral drugs into nanosystems has shown improved drug release and pharmacokinetic profile.     

The prospects for using (Q)SARs in a changing political environment--high expectations and a key role for the European Commission's joint research centre

Recent policy developments in the European union (EU) and within the Organisation for Economic Cooperation and Development (OECD) have placed increased emphasis on the use of structure-activity relationships (SARs) and quantitative structure-activity relationships (QSARs), collectively referred to as (Q)SARs, within various regulatory programmes for the assessment of chemicals and products. The most significant example within the EU is the European commission's proposal (of 29 October 2003) to introduce a new system for managing chemicals (called REACH), which calls for an increased use of (Q)SARs and other non-animal methods, especially for the assessment of low production volume chemicals. Another development within the EU is the Seventh Amendment to the Cosmetics Directive, which foresees the phasing out of animal testing on cosmetics, combined with the imposition of marketing bans on cosmetics that have been tested on animals after certain deadlines. At the same time, the Existing Chemicals programme within the OECD is investigating ways of increasing the use of chemical category approaches, which depend heavily on the use of (Q)SARs, activity-activity relationships and read-across. Such developments are placing an enormous challenge on industry, regulatory bodies, and on the European commission's Joint Research Centre (JRC), which is responsible for providing independent scientific advice to policy makers in the European Commission and the Member States. This paper reviews the different scientific and regulatory purposes for which reliable (Q)SARs could be used, and describes the current work of the JRC in providing scientific support for the development, validation and implementation of (Q)SARs.     

Global government applications of analogues,SARs and QSARs to predict aquatic toxicity,chemical or physical properties,environmental fate parameters and health effects of organic chemicals

Faced with the need to predict physical and chemical properties, environmental fate, ecological effects and health effects of organic chemicals in the absence of experimental data, several Government organizations have been applying analogues, Structure Activity Relationships (SARs) and Quantitative Structure Activity Relationships (QSARs) to develop those predictions. To establish some benchmarks for monitoring future increases in applications of analogues, SARs and QSARs by global Government organizations, this paper describes the current applications of analogues, SARs and QSARs by Australian, Canadian, Danish, European, German, Japanese, Netherlands, and United States Government organizations to predict physical and chemical properties, environmental fate, ecological effects and health effects of organic chemicals.     

Application of microcalorimetry to the formulation study

Isothermal microcalorimetry was used to evaluate excipient compatibility of solid dosage form. Oxybutynin hydrochloride and cefaclor were used as model drugs for compatibility test with excipients. The calorimetric data for compatibility test were compared with those of HPLC data. Evaluation of compatibility between drug and excipient of solid dosage form might be possible to use isothermal microcalorimetry instead of conventional method. By using microcalorimetric method, the evaluation of the compatibility between drug and excipient could be successfully performed with a simple operation in a short time. The application of the isothermal microcalorimetry would be useful for the screening test of the drug compatibility with excipients.     

An evaluation of selected global (Q)SARs/expert systems for the prediction of skin sensitisation potential

Skin sensitisation potential is an endpoint that needs to be assessed within the framework of existing and forthcoming legislation. At present, skin sensitisation hazard is normally identified using in vivo test methods, the favoured approach being the local lymph node assay (LLNA). This method can also provide a measure of relative skin sensitising potency which is essential for assessing and managing human health risks. One potential alternative approach to skin sensitisation hazard identification is the use of (Quantitative) structure activity relationships ((Q)SARs) coupled with appropriate documentation and performance characteristics. This represents a major challenge. Current thinking is that (Q)SARs might best be employed as part of a battery of approaches that collectively provide information on skin sensitisation hazard. A number of (Q)SARs and expert systems have been developed and are described in the literature. Here we focus on three models (TOPKAT, Derek for Windows and TOPS-MODE), and evaluate their performance against a recently published dataset of 211 chemicals. The current strengths and limitations of one of these models is highlighted, together with modifications that could be made to improve its performance. Of the models/expert systems evaluated, none performed sufficiently well to act as a standalone tool for hazard identification.     

Shuttle-mediated drug delivery to the brain

Advances in the field of shuttle-mediated drug delivery have been made in the last decade; however, the treatment of brain disorders still remains a great challenge because of the presence of the blood-brain barrier (BBB), a structure that limits the access of drugs to their site of action in the central nervous system. Several strategies have been proposed to enhance the transport of drugs across the BBB. In this Review, we focus on the vector-mediated approach, in which a drug is coupled to a molecule (shuttle) that has the ability to cross the BBB and deliver the drug to the brain.     

Global Government applications of analogues,SAR s and QSAR s to predict aquatic toxicity,chemical or physical properties,environmental fate parameters and health effects of organic chemicals

Faced with the need to predict physical and chemical properties, environmental fate, ecological effects and health effects of organic chemicals in the absence of experimental data, several Government organizations have been applying analogues, Structure Activity Relationships (SARs) and Quantitative Structure Activity Relationships (QSARs) to develop those predictions. To establish some benchmarks for monitoring future increases in applications of analogues, SARs and QSARs by global Government organizations, this paper describes the current applications of analogues, SARs and QSARs by Australian, Canadian, Danish, European, German, Japanese, Netherlands, and United States Government organizations to predict physical and chemical properties, environmental fate, ecological effects and health effects of organic chemicals.     

Multidrug Resistance (MDR): A Widespread Phenomenon in Pharmacological Therapies

Multidrug resistance is a leading concern in public health. It describes a complex phenotype whose predominant feature is resistance to a wide range of structurally unrelated cytotoxic compounds, many of which are anticancer agents. Multidrug resistance may be also related to antimicrobial drugs, and is known to be one of the most serious global public health threats of this century. Indeed, this phenomenon has increased both mortality and morbidity as a consequence of treatment failures and its incidence in healthcare costs. The large amounts of antibiotics used in human therapies, as well as for farm animals and even for fishes in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. It is not negligible that the ongoing COVID-19 pandemic may further contribute to antimicrobial resistance. In this paper, multidrug resistance and antimicrobial resistance are underlined, focusing on the therapeutic options to overcome these obstacles in drug treatments. Lastly, some recent studies on nanodrug delivery systems have been reviewed since they may represent a significant approach for overcoming resistance.     

An evaluation of selected global (Q)SARs/expert systems for the prediction of skin sensitisation potential

Skin sensitisation potential is an endpoint that needs to be assessed within the framework of existing and forthcoming legislation. At present, skin sensitisation hazard is normally identified using in vivo test methods, the favoured approach being the local lymph node assay (LLNA). This method can also provide a measure of relative skin sensitising potency which is essential for assessing and managing human health risks. One potential alternative approach to skin sensitisation hazard identification is the use of (Quantitative) structure activity relationships ((Q)SARs) coupled with appropriate documentation and performance characteristics. This represents a major challenge. Current thinking is that (Q)SARs might best be employed as part of a battery of approaches that collectively provide information on skin sensitisation hazard. A number of (Q)SARs and expert systems have been developed and are described in the literature. Here we focus on three models (TOPKAT, Derek for Windows and TOPS-MODE), and evaluate their performance against a recently published dataset of 211 chemicals. The current strengths and limitations of one of these models is highlighted, together with modifications that could be made to improve its performance. Of the models/expert systems evaluated, none performed sufficiently well to act as a standalone tool for hazard identification.