Repurposing – second life for drugs

Drug repurposing refers to finding new indications for existing drugs. The paradigm shift from traditional drug discovery to drug repurposing is driven by the fact that new drug pipelines are getting dried up because of mounting Research & Development (R&D) costs, long timeline for new drug development, low success rate for new molecular entities, regulatory hurdles coupled with revenue loss from patent expiry and competition from generics. Anaemic drug pipelines along with increasing demand for newer effective, cheaper, safer drugs and unmet medical needs call for new strategies of drug discovery and, drug repurposing seems to be a promising avenue for such endeavours. Drug repurposing strategies have progressed over years from simple serendipitous observations to more complex computational methods in parallel with our ever-growing knowledge on drugs, diseases, protein targets and signalling pathways but still the knowledge is far from complete. Repurposed drugs too have to face many obstacles, although lesser than new drugs, before being successful.

Designing HDAC-PROTACs: lessons learned so far

Proteolysis-targeting chimeras (PROTACs) are a powerful tool to hijack the endogenous ubiquitin-proteasome system (UPS) and to degrade the intracellular proteins of therapeutic importance. Recently, two heterobifunctional degraders targeting hormone receptors headed into Phase II clinical trials. Compared to traditional drug design and common modes of action, the PROTAC approach offers new opportunities for the drug research field. Histone deacetylase inhibitors (HDACi) are well-established drugs for the treatment of hematological malignancies. The integration of HDAC binding motifs in PROTACs explores the possibility of targeted, chemical HDAC degradation. This review provides an overview and a perspective about the key steps in the structure development of HDAC–PROTACs. In particular, the influence of the three canonical PROTAC elements on HDAC–PROTAC efficacy and selectivity are discussed, the HDACi, the linker and the E3 ligase ligand.

Considerations and Challenges for Sex-Aware Drug Repurposing

Sex differences are essential factors in disease etiology and manifestation in many diseases such as cardiovascular disease, cancer, and neurodegeneration (1). The biological influence of sex differences (including genomic, epigenetic, hormonal, immunological, and metabolic differences between males and females) and the lack of biomedical studies considering sex differences in their study design has led to several policies. For example, the National Institute of Health’s (NIH) sex as a biological variable (SABV) and Sex and Gender Equity in Research (SAGER)) policies to motivate researchers to consider sex differences (2). However, drug repurposing, a promising alternative to traditional drug discovery by identifying novel uses for FDA-approved drugs, lacks sex-aware methods that can improve the identification of drugs that have sex-specific responses (1,3–5). Sex-aware drug repurposing methods either select drug candidates that are more efficacious in one sex or deprioritize drug candidates based on if they are predicted to cause a sex-bias adverse event (SBAE), unintended therapeutic effects that are more likely to occur in one sex. Computational drug repurposing methods are encouraging approaches to develop for sex-aware drug repurposing because they can prioritize sex-specific drug candidates or SBAEs at lower cost and time than traditional drug discovery. Sex-aware methods currently exist for clinical, genomic, and transcriptomic information (3,6,7). They have not expanded to other data types, such as DNA variation, which has been beneficial in other drug repurposing methods that do not consider sex (8). Additionally, some sex-aware methods suffer from poorer performance because a disproportionate number of male and female samples are available to train computational methods (3). However, there is development potential for several different categories (i.e., data mining, ligand binding predictions, molecular associations, and networks). Low-dimensional representations of molecular association and network approaches are also especially promising candidates for future sex-aware drug repurposing methodologies because they reduce the multiple hypothesis testing burden and capture sex-specific variation better than the other methods (9,10). Here we review how sex influences drug response, the current state of drug repurposing including with respect to sex-bias drug response, and how model organism study design choices influence drug repurposing validation.

Pharmaceutical care in medical homeopathic service in public health in Jundiaí (SP), Brazil

Pharmaceutical care is a concept already well established, but its application presents difficulties in homeopathy since homeopathic medicines have no the same indications as traditional drug classes. In recent decades the Brazilian Homeopathic Pharmacy presented a major development in the area of Pharmacotechnics, exemplified by the creation of local and national associations, the publication of technical texts and the fact that homeopathic medicines are, almost entirely, manipulated in pharmacies. It is also important to develop a pharmaceutical care in homeopathy, optimizing the activities of the medical homeopath and extending the service to the population. For two years, in a medical education and clinical service conducted at the Medical Faculty of Jundiaí, and supported by the Public Medical Service (SUS), three pharmacists and one pharmacy student, were responsible for pre and post consultation and dispensing of medicines. The objectives of this paper are to document the activities of pharmaceutical care, in order to encourage the activities of pharmacists in homeopathy. We developed a form for interviews as a pre-consultations. In the first consultation, it was used to record the identification data of the patient, the symptoms that brought him to the consultation, information about the presence of several physicians in the consultation and about the homeopathic treatment. In subsequent consultations, it was used to investigate the changes that have occurred since the last visit to the service. In post-consultation, the dispensation of the medication was done, with information about its use and conservation. The forms were given to the physicians and kept for future reference along with the clinical records of patients. As a result there was a positive reaction on the part of patients, probably because they felt more confident and instructed about the homeopathic treatment. The physicians referred in a positive manner about the help of pharmacists. Pharmacists have the opportunity to closely follow the changes in the health of patients, verifying the effectiveness of homeopathic treatment. The relationship between doctors and pharmacists developed in a positive way. Unfortunately, despite numerous cases of improvement of patients' symptoms, as well as its appreciation for homeopathic care, homeopathic service ended abruptly in the first half of 2011 due to lack of support from the Medical Faculty and public health service of that municipality, demonstrating once again the fragility of homeopathic services.

Drug Discovery for Mycobacterium tuberculosis Using Structure-Based Computer-Aided Drug Design Approach

Developing new, more effective antibiotics against resistant Mycobacterium tuberculosis that inhibit its essential proteins is an appealing strategy for combating the global tuberculosis (TB) epidemic. Finding a compound that can target a particular cavity in a protein and interrupt its enzymatic activity is the crucial objective of drug design and discovery. Such a compound is then subjected to different tests, including clinical trials, to study its effectiveness against the pathogen in the host. In recent times, new techniques, which involve computational and analytical methods, enhanced the chances of drug development, as opposed to traditional drug design methods, which are laborious and time-consuming. The computational techniques in drug design have been improved with a new generation of software used to develop and optimize active compounds that can be used in future chemotherapeutic development to combat global tuberculosis resistance. This review provides an overview of the evolution of tuberculosis resistance, existing drug management, and the design of new anti-tuberculosis drugs developed based on the contributions of computational techniques. Also, we show an appraisal of available software and databases on computational drug design with an insight into the application of this software and databases in the development of anti-tubercular drugs. The review features a perspective involving machine learning, artificial intelligence, quantum computing, and CRISPR combination with available computational techniques as a prospective pathway to design new anti-tubercular drugs to combat resistant tuberculosis.

Nanocarriers for Inner Ear Disease Therapy

Hearing loss is a common disease due to sensory loss caused by the diseases in the inner ear. The development of delivery systems for inner ear disease therapy is important to achieve high efficiency and reduce side effects. Currently, traditional drug delivery systems exhibit the potential to be used for inner ear disease therapy, but there are still some drawbacks. As nanotechnology is developing these years, one of the solutions is to develop nanoparticle-based delivery systems for inner ear disease therapy. Various nanoparticles, such as soft material and inorganic-based nanoparticles, have been designed, tested, and showed controlled delivery of drugs, improved targeting property to specific cells, and reduced systemic side effects. In this review, we summarized recent progress in nanocarriers for inner ear disease therapy. This review provides useful information on developing promising nanocarriers for the efficient treatment of inner ear diseases and for further clinical applications for inner ear disease therapy.

Application of Nanomaterials in Neurodegenerative Diseases

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease are very harmful brain lesions. Due to the difficulty in obtaining therapeutic drugs, the best treatment for neurodegenerative diseases is often not available. In addition, the bloodbrain barrier can effectively prevent the transfer of cells, particles and macromolecules (such as drugs) in the brain, resulting in the failure of the traditional drug delivery system to provide adequate cellular structure repair and connection modes, which are crucial for the functional recovery of neurodegenerative diseases. Nanomaterials are designed to carry drugs across the blood-brain barrier for targets. Nanotechnology uses engineering materials or equipment to interact with biological systems at the molecular level to induce physiological responses through stimulation, response and target site interactions, while minimizing the side effects, thus revolutionizing the treatment and diagnosis of neurodegenerative diseases. Some magnetic nanomaterials play a role as imaging agents or nanoprobes for Magnetic Resonance Imaging to assist in the diagnosis of neurodegenerative diseases. Although the current research on nanomaterials is not as useful as expected in clinical applications, it achieves a major breakthrough and guides the future development direction of nanotechnology in the application of neurodegenerative diseases. This review briefly discusses the application and advantages of nanomaterials in neurodegenerative diseases. Data for this review were identified by searches of PubMed, and references from relevant articles published in English between 2015 and 2019 using the search terms “nanomaterials”, “neurodegenerative diseases” and “blood-brain barrier”.

In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma

Background: Glioblastoma represents the most common primary brain tumor in adults. Despite technological advances, patients with this disease typically die within 1–2 years after diagnosis. In the search for novel therapeutics, drug repurposing has emerged as an alternative to traditional drug development pipelines, potentially facilitating and expediting the transition from drug discovery to clinical application. In a drug repurposing effort, the original CUSP9 and its derivatives CUSP9* and CUSP9v3 were developed as combinations of nine non-oncological drugs combined with metronomic low-dose temozolomide. Methods: In this work, we performed pre-clinical testing of CUSP9v3 in different established, primary cultured and stem-like glioblastoma models. In addition, eight patients with heavily pre-treated recurrent glioblastoma received the CUSP9v3 regime on a compassionate use basis in a last-ditch effort. Results: CUSP9v3 had profound antiproliferative and pro-apoptotic effects across all tested glioblastoma models. Moreover, the cells’ migratory capacity and ability to form tumor spheres was drastically reduced. In vitro, additional treatment with temozolomide did not significantly enhance the antineoplastic activity of CUSP9v3. CUSP9v3 was well-tolerated with the most frequent grade 3 or 4 adverse events being increased hepatic enzyme levels. Conclusions: CUSP9v3 displays a strong anti-proliferative and anti-migratory activity in vitro and seems to be safe to apply to patients. These data have prompted further investigation of CUSP9v3 in a phase Ib/IIa clinical trial (NCT02770378).

A Novel Curcumin-Based Drug Powder Inhalation Medicine for Chronic Obstructive Pulmonary Disease

The dry powder inhaler is a new form of drug delivery that is widely used as an alternative to traditional drug delivery methods, addressing the shortcomings of traditional drug delivery methods and obtaining better therapeutic results. This mode of delivery is also one of the most rational ways to treat pulmonary diseases such as chronic obstructive pulmonary disease (COPD). Curcumin, a natural polyphenol, has been shown to be effective in the treatment of COPD. In this study, different concentrations of curcumin ethanol solution were spray dried with mannitol as a carrier to obtain dry powder particles with different particle size distribution for the preparation of curcumin dry powder inhaler. The solubility and physicochemical properties were further characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy. The characterization results showed that the product obtained in the experiment had reasonable particle size distribution and excellent solubility properties, which were positive for the treatment of COPD or other pulmonary diseases.

Review on Nanotechnology and its utilization in Pharmaceuticals

Nanotechnology is the study of tiny structures ranging in size from 0.1 to 100 nanometers. It includes biophysics, molecular biology, and bioengineering, as well as medical subspecialties such as cardiology, ophthalmology, endocrinology, oncology, and immunology. Pharmaceutical Nanotechnology combines the methods and ideas of nanoscience and nanomedicine with pharmacy to create novel medication delivery systems that transcend the limitations of traditional drug delivery systems. The purpose of this article is to provide an overview of nanotechnology and its uses in the pharmaceutical industry.