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Appropriate dosing of cystine-binding thiol drugs in the management of cystinuria has been based on clinical stone activity. When new stones form, the dose is increased. Currently, there is no method of measuring urinary drug levels to guide the titration of therapy. Increasing cystine capacity, a measure of cystine solubility, has been promoted as a method of judging the effects of therapy. In this study, we gave increasing doses of tiopronin or d-penicillamine, depending on the patients’ own prescriptions, to ten patients with cystinuria and measured cystine excretion and cystine capacity. The doses were 0, 1, 2, 3 g per day, given in two divided doses, and administered in a random order. Going from 0 to 1 g/day led to an increase in cystine capacity from − 39.1 to 130.4 mg/L (P < 0.009) and decreased 24 h cystine excretion from 1003.9 to 834.8 mg/day (P = 0.039). Increasing the doses from 1 to 2 to 3 g/day had no consistent or significant effect to further increase cystine capacity or decrease cystine excretion. Whether doses higher than 1 g/day have additional clinical benefit is not clear from this study. Limiting doses might be associated with fewer adverse effects without sacrificing the benefit of higher doses if higher doses do not offer clinical importance. However, trials with stone activity as an outcome would be desirable.

Hydrotropes are small molecules that solubilize hydrophobic molecules in aqueous solutions. Typically, hydrotropes are amphiphilic molecules and differ from classical surfactants in that they have low cooperativity of aggregation and work at molar concentrations. Here, we show that adenosine triphosphate (ATP) has properties of a biological hydrotrope. It can both prevent the formation of and dissolve previously formed protein aggregates. This chemical property is manifested at physiological concentrations between 5 and 10 millimolar. Therefore, in addition to being an energy source for biological reactions, for which micromolar concentrations are sufficient, we propose that millimolar concentrations of ATP may act to keep proteins soluble. This may in part explain why ATP is maintained in such high concentrations in cells.

Biological variability poses significant challenges in the development of effective therapeutics, particularly when it comes to drug solubility and bioavailability. Poor solubility across varying physiological conditions often leads to reduced absorption and inconsistent therapeutic outcomes. This review examines how nanotechnology, especially through the use of nanomaterials and magnetic nanoparticles, offers innovative solutions to enhance drug solubility and bioavailability. This comprehensive review focuses on recent advancements and approaches in nanotechnology. We highlight both the successes and remaining challenges in this field, emphasizing the role of continued innovation. Future research should prioritize developing universal therapeutic solutions, conducting interdisciplinary research, and leveraging personalized nanomedicine to address biological variability.

Solubility, bioavailability, permeation, polymorphism, and stability concerns associated to solid-state pharmaceuticals demand for effective solutions. To overcome some of these drawbacks, ionic liquids (ILs) have been investigated as solvents, reagents, and anti-solvents in the synthesis and crystallization of active pharmaceutical ingredients (APIs), as solvents, co-solvents and emulsifiers in drug formulations, as pharmaceuticals (API-ILs) aiming liquid therapeutics, and in the development and/or improvement of drug-delivery-based systems. The present review focuses on the use of ILs in the pharmaceutical field, covering their multiple applications from pharmaceutical synthesis to drug delivery. The most relevant research conducted up to date is presented and discussed, together with a critical analysis of the most significant IL-based strategies in order to improve the performance of therapeutics and drug delivery systems.

While each of the two key parameters of oral drug absorption, the solubility and the permeability, has been comprehensively studied separately, the relationship and interplay between the two have been largely ignored. For instance, when formulating a low-solubility drug using various solubilization techniques: what are we doing to the apparent permeability when we increase the solubility? Permeability is equal to the drug’s diffusion coefficient through the membrane times the membrane/aqueous partition coefficient divided by the membrane thickness. The direct correlation between the intestinal permeability and the membrane/aqueous partitioning, which in turn is dependent on the drug’s apparent solubility in the GI milieu, suggests that the solubility and the permeability are closely associated, exhibiting a certain interplay between them, and the current view of treating the one irrespectively of the other may not be sufficient. In this paper, we describe the research that has been done thus far, and present new data, to shed light on this solubility–permeability interplay. It has been shown that decreased apparent permeability accompanies the solubility increase when using different solubilization methods. Overall, the weight of the evidence indicates that the solubility–permeability interplay cannot be ignored when using solubility-enabling formulations; looking solely at the solubility enhancement that the formulation enables may be misleading with regards to predicting the resulting absorption, and hence, the solubility–permeability interplay must be taken into account to strike the optimal solubility–permeability balance, in order to maximize the overall absorption.

The unique properties of ionic liquids (ILs), such as structural tunability, good solubility, chemical/thermal stability, favorable biocompatibility, and simplicity of preparation, have led to a wide range of applications in the pharmaceutical and biomedical fields. ILs can not only speed up the chemical reaction process, improve the yield, and reduce environmental pollution but also improve many problems in the field of medicine, such as the poor drug solubility, product crystal instability, poor biological activity, and low drug delivery efficiency. This paper presents a systematic and concise analysis of the recent advancements and further applications of ILs in the pharmaceutical field from the aspects of drug synthesis, drug analysis, drug solubilization, and drug crystal engineering. Additionally, it explores the biomedical field, covering aspects such as drug carriers, stabilization of proteins, antimicrobials, and bioactive ionic liquids.

Biopharmaceutical classification system (BCS) is an advanced tool used for classifying medicines based on dissolution, water solubility, and intestinal permeability, which affect the absorption of active pharmaceutical ingredients (API) from immediate-release solid oral forms. It is useful to the formulation researchers to develop novel dosage forms based on modernistic rather than experimental approaches. The current review focuses on the fundamentals, objectives, guidance of BCS, characteristics of BCS drugs, their importance and applications of BCS. This review explains the challenges in drug development in terms of solubility and in vivo disposition. In the current review, new strategies for improving BCS II drug solubility as well as biopharmaceutical drug disposition properties which are utilized throughout the early stages of drug development and commercialization are mainly discussed.

Transactive response DNA-binding (TDP-43) protein is the dominant disease protein in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP). Identification of mutations in the gene encoding TDP-43 (TARDBP) in familial ALS confirms a mechanistic link between misaccumulation of TDP-43 and neurodegeneration and provides an opportunity to study TDP-43 proteinopathies in human neurons generated from patient fibroblasts by using induced pluripotent stem cells (iPSCs). Here, we report the generation of iPSCs that carry the TDP-43 M337V mutation and their differentiation into neurons and functional motor neurons. Mutant neurons had elevated levels of soluble and detergent-resistant TDP-43 protein, decreased survival in longitudinal studies, and increased vulnerability to antagonism of the PI3K pathway. We conclude that expression of physiological levels of TDP-43 in human neurons is sufficient to reveal a mutation-specific cell-autonomous phenotype and strongly supports this approach for the study of disease mechanisms and for drug screening.

Growth and carbon (C) fluxes are severely altered in plants exposed to soil water deficit. Correspondingly, it has been suggested that plants under water deficit suffer from C shortage. In this study, we test this hypothesis in Arabidopsis (Arabidopsis thaliana) by providing an overview of the responses of growth, C balance, metabolites, enzymes of the central metabolism, and a set of sugar-responsive genes to a sustained soil water deficit. The results show that under drought, rosette relative expansion rate is decreased more than photosynthesis, leading to a more positive C balance, while root growth is promoted. Several soluble metabolites accumulate in response to soil water deficit, with K⁺ and organic acids as the main contributors to osmotic adjustment. Osmotic adjustment costs only a small percentage of the daily photosynthetic C fixation. All C metabolites measured (not only starch and sugars but also organic acids and amino acids) show a diurnal turnover that often increased under water deficit, suggesting that these metabolites are readily available for being metabolized in situ or exported to roots. On the basis of 30 enzyme activities, no in-depth reprogramming of C metabolism was observed. Water deficit induces a shift of the expression level of a set of sugar-responsive genes that is indicative of increased, rather than decreased, C availability. These results converge to show that the differential impact of soil water deficit on photosynthesis and rosette expansion results in an increased availability of C for the roots, an increased turnover of C metabolites, and a low-cost C-based osmotic adjustment, and these responses are performed without major reformatting of the primary metabolism machinery.

The development of effective drug formulations and delivery systems for newly developed or marketed drug molecules remains a significant challenge. These drugs can exhibit polymorphic conversion, poor bioavailability, and systemic toxicity, and can be difficult to formulate with traditional organic solvents due to acute toxicity. Ionic liquids (ILs) are recognized as solvents that can improve the pharmacokinetic and pharmacodynamic properties of drugs. ILs can address the operational/functional challenges associated with traditional organic solvents. However, many ILs are non-biodegradable and inherently toxic, which is the most significant challenge in developing IL-based drug formulations and delivery systems. Biocompatible ILs comprising biocompatible cations and anions mainly derived from bio-renewable sources are considered a green alternative to both conventional ILs and organic/inorganic solvents. This review covers the technologies and strategies developed to design biocompatible ILs, focusing on the design of biocompatible IL-based drug formulations and delivery systems, and discusses the advantages of these ILs in pharmaceutical and biomedical applications. Furthermore, this review will provide guidance on transitioning to biocompatible ILs rather than commonly used toxic ILs and organic solvents in fields ranging from chemical synthesis to pharmaceutics.