Using human samples in proteomics-based drug development: bioethical aspects

Human samples and related medical data are expected to play an elevated role in application-based biomedical proteomics research. Against this framework, some facts should be kept in mind by academic and industrial researchers: international framework conditions on the use of human samples for research purposes are heterogeneous. For example, the value added by the use of human samples for product development is significant and the patient’s personal and property rights may be affected. The body of national laws is growing and these laws are binding; guidelines published by international organizations should be respected. The most important aspect regards the informed consent of the patient, which is addressed in detail.     

Endocytosis in cellular uptake of drug delivery vectors: Molecular aspects in drug development

Drug delivery vectors are widely applied to increase drug efficacy while reducing the side effects and potential toxicity of a drug. They allow for patient-tailored therapy, dose titration, and therapeutic drug monitoring. A major part of drug delivery systems makes use of large nanocarriers: liposomes or virus-like particles (VLPs). These systems allow for a relatively large amount of cargo with good stability of vectors, and they offer multiple options for targeting vectors in vivo. Here we discuss endocytic pathways that are available for drug delivery by large nanocarriers. We focus on molecular aspects of the process, including an overview of potential molecular targets for studies of drug delivery vectors and for future solutions allowing targeted drug delivery.     

Accurate prediction of human drug toxicity: a major challenge in drug development

Over the past decades, a number of drugs have been withdrawn or have required special labeling due to adverse effects observed post-marketing. Species differences in drug toxicity in preclinical safety tests and the lack of sensitive biomarkers and nonrepresentative patient population in clinical trials are probable reasons for the failures in predicting human drug toxicity. It is proposed that toxicology should evolve from an empirical practice to an investigative discipline. Accurate prediction of human drug toxicity requires resources and time to be spent in clearly defining key toxic pathways and corresponding risk factors, which hopefully, will be compensated by the benefits of a lower percentage of clinical failure due to toxicity and a decreased frequency of market withdrawal due to unacceptable adverse drug effects.     

Using photolabile ligands in drug discovery and development

Photoactivatable ligands are important tools used in drug discovery and drug development. These ligands enable researchers to identify the targets of drugs, to determine the affinity and selectivity of the drug-target interaction, and to identify the binding site on the target. Examples are presented from three fundamentally different approaches: (1) photoaffinity labeling of target macromolecules; (2) photoactivation and release of 'caged ligands'; and (3) photoimmobilization of ligands onto surfaces.     

Chiral aspects of metabolism of antiinflammatory drug flobufen in human hepatocytes

The metabolism of the nonsteroidal antiinflammatory drug flobufen, 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid, was studied in primary cultures of human hepatocytes prepared by two-step collagenase perfusion of livers from four donors. Racemic flobufen or its individual enantiomers, R-(+)- and S-(-)-flobufen were used as substrates. Aliquots of culture medium were collected during 24-h incubation. The time-dependent disappearance of flobufen enantiomers and the formation of metabolites (stereoisomers of dihydroflobufen (DHF)) in hepatocytes were measured by chiral HPLC. The reduction of flobufen in human hepatocytes was stereoselective ((+)-R-flobufen was preferentially metabolized) and stereospecific ((2R;4S)-DHF and (2S;4S)-DHF stereoisomers were mostly formed). Although the structure of flobufen is different from the profens (2-arylpropionates), flobufen undergoes chiral inversion in human hepatocytes. The inversion of R-(+)-flobufen to S-(-)-flobufen predominates. The individual DHF stereoisomers were incubated in hepatocyte cultures and their biotransformation studied. The unidirectional chiral inversion of (2S;4S)-DHF to (2R;4S)-DHF and (2R;4R)-DHF to (2S;4R)-DHF was observed. Stereoselective oxidation of the DHFs to flobufen was also detected. Thus, flobufen metabolism in primary cultures of human hepatocytes is much more complicated (via chiral inversion and DHF re-oxidation) than was presumed from a preliminary achiral point of view.     

A human approach to drug development: opportunities and limitations

The pharmaceutical industry is failing in its primary function, with increasing expenditure and decreased output in terms of new medicines brought to market. It cannot carry on as it is, without sliding into a terminal decline. It must, therefore, take some positive steps toward addressing its problems. We do not have to look far to see one very obvious problem, namely, the industry's continuing reliance on nonhuman biology as the basis of its evaluation of potential safety and efficacy. The time has come to focus on the relevant, and to realise that more human-based testing is essential, if the industry is to survive as a source of innovation in drug therapy. This can incorporate earlier clinical testing, in the form of microdosing, and promotion of the development of more-powerful computational approaches based on human information. Fortunately, headway is being made in both approaches. However, a problem remains in the lack of functional evaluation of human tissues, where the lack of commitment, and the inadequacy of the tissue resource itself, are hampering any serious developments. An outline of a collaborative scheme is proposed, that will address this issue, central to which is improved access to research tissues from heart-beating organ donors.     

The use of functional human tissues in drug development

Drug development currently depends on animal models to provide an accurate prediction of human physiology and pathophysiology. However, as is clear from clinical trial failures during phases II and III, such in vivo models do not always predict the effects that a drug can elicit in humans. Tests with human tissues, which are obviously considered to be the closest model of human in vivo function, could fill the gap between animal-based tests and trials in patients. Despite clear advantages, logistical and ethical barriers prevent fresh human tissues from being widely used during drug development. Biopta is aiming to make human tissue testing a regular element of drug development, and works to lower the barriers surrounding the availability of tissue and practicalities of experimental work.     

The use of functional human tissues in drug development

Fresh, functional human tissues have long been considered the closest possible model of human in vivo function and can be used to measure a wide range of pharmacological responses. Despite this, relatively little drug development is conducted using fresh human tissue because of the logistical and ethical difficulties surrounding the availability of tissue and practicalities of experimental work. Most tests of drug activity require a living test system comprising cells, tissues or whole organisms. In some instances, “living” (fresh) human tissues have the potential to reduce or replace animal tests through superior prediction of drug safety and efficacy. Before functional human tissue tests become a routine part of drug development, two factors must co-exist. Firstly, organisations such as Biopta must continue to create compelling evidence that human tissues are more predictive than alternative models; such evidence will drive demand from the pharmaceutical industry for human tissue-based tests. Secondly, the vast number of tissues and organs residual to surgery or unsuitable for transplant must be routinely consented for medical research and made available to all researchers in an equitable and timely manner. This requires a concerted effort throughout the NHS and consistent demand as well as financial support from researchers, particularly within industry. It is our view that the next 5–10 years will generate compelling evidence of the value of functional human tissue-based tests and recognition that more efficient use of residual or non-transplantable tissues and organs is an urgent priority for the development of new medicines.     

Potential drug development candidates for human soil-transmitted helminthiases

Background

Few drugs are available for soil-transmitted helminthiasis (STH); the benzimidazoles albendazole and mebendazole are the only drugs being used for preventive chemotherapy as they can be given in one single dose with no weight adjustment. While generally safe and effective in reducing intensity of infection, they are contra-indicated in first-trimester pregnancy and have suboptimal efficacy against Trichuris trichiura. In addition, drug resistance is a threat. It is therefore important to find alternatives.

Methodology

We searched the literature and the animal health marketed products and pipeline for potential drug development candidates. Recently registered veterinary products offer advantages in that they have undergone extensive and rigorous animal testing, thus reducing the risk, cost and time to approval for human trials. For selected compounds, we retrieved and summarised publicly available information (through US Freedom of Information (FoI) statements, European Public Assessment Reports (EPAR) and published literature). Concomitantly, we developed a target product profile (TPP) against which the products were compared.

Principal Findings

The paper summarizes the general findings including various classes of compounds, and more specific information on two veterinary anthelmintics (monepantel, emodepside) and nitazoxanide, an antiprotozoal drug, compiled from the EMA EPAR and FDA registration files.

Conclusions/Significance

Few of the compounds already approved for use in human or animal medicine qualify for development track decision. Fast-tracking to approval for human studies may be possible for veterinary compounds like emodepside and monepantel, but additional information remains to be acquired before an informed decision can be made.     

Culture development for human embryonic stem cell propagation: molecular aspects and challenges

Basic fibroblast growth factor and members of the transforming growth factor-beta superfamily are important regulators of human embryonic stem cell (hESC) self-renewal. Extensive cross-talk between the intracellular signaling pathways activated by these factors contributes to maintenance of the undifferentiated hESC state. Understanding the molecular regulation of hESC self-renewal will facilitate the design of improved systems for hESC propagation and provide a foundation for strategies to direct the differentiation of hESCs to clinically relevant cell types.     

The regulation of human blastoid research: A bioethical discussion of the limits of regulation

The creation of human blastoids holds great potential for research on early human development but also raises considerations about the ethics of such research and its regulation. Subject Categories: Development, Economics, Law & Politics

Developmental research has made considerable progress modeling either part of or the entire embryonic development of both humans and non‐human animals. A major step forward was the ability to grow blastocyst‐like structures from pluripotent stem cells: these structures, known as “blastoids,” mimic early embryonic development up to and potentially beyond the blastocyst stage 5–6 days after the first cell division. Blastoids have attracted considerable attention as an effective research tool to understand early human development and to elucidate the causes of infertility, teratogenesis, and other developmental abnormalities.

… many scientists see the use of human blastoids as an exciting scientific opportunity, as it may help to reduce the need for human embryos in research.

Until now, research with blastoids has mainly studied early development in mice, but, as of 2021, research results are also being reported from human blastoids (see “Further Reading”). Indeed, many scientists see the use of human blastoids as an exciting scientific opportunity, as it may help to reduce the need for human embryos in research (Ravindran, ²⁰²¹). However, as with any research that uses human embryos or human stem cells derived from embryos, human blastoid research raises ethical questions and is subject to regulation and approval. The latest ISSCR guidelines state that “[f]orms of research with embryos … and stem cell‐based embryo models … are permissible only after review and approval through a specialized scientific and ethics review process” (ISSCR, ²⁰²¹). Thus, although blastoids are models of embryonic development, they are currently considered to require the same or similar ethical considerations as blastocysts or cells derived from human embryos. In fact, Australia made a decision to regulate blastoid research in the same manner as research on human embryos (Australia NHMRC, ²⁰²¹).     

Chimpanzees in AIDS research: A biomedical and bioethical perspective

The present article represents a consensus view of the appropriate utilization of chimpanzees in AIDS research arrived at as a result of a meeting of a group of scientists involved in AIDS research with chimpanzees and bioethicists. The paper considers which types of studies are scientifically justifiable in this species, the conditions under which such studies should be carried out, and the conditions which should be encouraged for post-experimental retirement of these animals.     

Overview: Evaluation of metabolism-based drug toxicity in drug development

Drug metabolism can be a key determinant of drug toxicity. A nontoxic parent drug may be biotransformed by drug metabolizing enzymes to toxic metabolites (metabolic activation). Conversely, a toxic drug may be biotransformed to nontoxic metabolites (detoxification). The approaches to evaluate metabolism-based drug toxicity include the identification of toxic metabolites and the evaluation of toxicity in metabolically competent and metabolically compromised systems. A clear understanding of the role of drug metabolism in toxicity can aid the identification of risk factors that may potentiate drug toxicity, and may provide key information for the development of safe drugs.     

Microscale culture of human liver cells for drug development

Tissue function depends on hierarchical structures extending from single cells ( approximately 10 microm) to functional subunits (100 microm-1 mm) that coordinate organ functions. Conventional cell culture disperses tissues into single cells while neglecting higher-order processes. The application of semiconductor-driven microtechnology in the biomedical arena now allows fabrication of microscale tissue subunits that may be functionally improved and have the advantages of miniaturization. Here we present a miniaturized, multiwell culture system for human liver cells with optimized microscale architecture that maintains phenotypic functions for several weeks. The need for such models is underscored by the high rate of pre-launch and post-market attrition of pharmaceuticals due to liver toxicity. We demonstrate utility through assessment of gene expression profiles, phase I/II metabolism, canalicular transport, secretion of liver-specific products and susceptibility to hepatotoxins. The combination of microtechnology and tissue engineering may enable development of integrated tissue models in the so-called 'human on a chip'.