Dosing Cariprazine Within and Beyond Clinical Trials: Recommendations for the Treatment of Schizophrenia

Although the optimal dosing of an antipsychotic medication is known to be essential in the long-term management of schizophrenia, in case of novel drugs such as cariprazine, determining the right dosing strategy is not that simple. Without decades of experience with a particular compound, evidence regarding dosing and titration comes primarily from double-blind, placebo controlled clinical trials that are not necessarily mirroring the real-life experiences of doctors. Via summarizing data from both clinical data (n = 3275) and real-world evidence (observational study n = 116, case studies n = 29), this perspective paper aims to shed a light on the appropriate dosing strategies of cariprazine from treatment initiation through switching strategies to concomitant medications.

Multiparameter Optimization of Trypanocidal Cruzain Inhibitors With In Vivo Activity and Favorable Pharmacokinetics

Cruzain, the main cysteine protease of Trypanosoma cruzi, plays key roles in all stages of the parasite’s life cycle, including nutrition acquisition, differentiation, evasion of the host immune system, and invasion of host cells. Thus, inhibition of this validated target may lead to the development of novel drugs for the treatment of Chagas disease. In this study, a multiparameter optimization (MPO) approach, molecular modeling, and structure-activity relationships (SARs) were employed for the identification of new benzimidazole derivatives as potent competitive inhibitors of cruzain with trypanocidal activity and suitable pharmacokinetics. Extensive pharmacokinetic studies enabled the identification of metabolically stable and permeable compounds with high selectivity indices. CYP3A4 was found to be involved in the main metabolic pathway, and the identification of metabolic soft spots provided insights into molecular optimization. Compound 28, which showed a promising trade-off between pharmacodynamics and pharmacokinetics, caused no acute toxicity and reduced parasite burden both in vitro and in vivo.

Phytocompound Mediated Blockage of Quorum Sensing Cascade in ESKAPE Pathogens

Increased resistance of Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter sp. (ESKAPE) pathogens against various drugs has enhanced the urge for the development of alternate therapeutics. Quorum sensing (QS) is a density dependent cell-to-cell communication mechanism responsible for controlling pathogenicity with the regulation of gene expression. Thus, QS is considered a potential target for the development of newer anti-biofilm agents that do not depend on the utilization of antibiotics. Compounds with anti-QS effects are known as QS inhibitors (QSIs), and they can inhibit the QS mechanism that forms the major form in the development of bacterial pathogenesis. A diverse array of natural compounds provides a plethora of anti-QS effects. Over recent years, these natural compounds have gained importance as new strategies for combating the ESKAPE pathogens and inhibiting the genes involved in QS. Different pharmacognostical and pharmacological studies have been carried out so far for identification of novel drugs or for the discovery of their unique structures that may help in developing more effective anti-biofilm therapies. The main objective of this review is to discuss the various natural compounds, so far identified and their employed mechanisms in hindering the genes responsible for QS leading to bacterial pathogenesis.

Identification of Novel Chemical Scaffolds that Inhibit the Growth of Mycobacterium tuberculosis in Macrophages

Mycobacterium tuberculosis is an important global pathogen for which new drugs are urgently required. The ability of the organism to survive and multiply within macrophages may contribute to the lengthy treatment regimen with multiple drugs that are required to cure the infection. We screened the MyriaScreen II diversity library of 10,000 compounds to identify novel inhibitors of M. tuberculosis growth within macrophage-like cells using high content analysis. Hits were selected which inhibited the intramacrophage growth of M. tuberculosis without significant cytotoxicity to infected macrophages. We selected and prioritized compound series based on their biological and physicochemical properties and the novelty of the chemotypes. We identified five chemical classes of interest and conducted limited catalog structure-activity relationship studies to determine their tractability. We tested activity against intracellular and extracellular M. tuberculosis, as well as cytoxicity against murine RAW264.7 and human HepG2 cells. Benzene amide ethers, thiophene carboxamides and thienopyridines were only active against intracellular bacteria, whereas the phenylthiourea series was also active against extracellular bacteria. One member of a phenyl pyrazole series was moderately active against extracellular bacteria. We identified the benzene amide ethers as an interesting series for further work. These new compound classes serve as starting points for the development of novel drugs to target intracellular M. tuberculosis.

Ethnic Use, Phytochemistry, and Pharmacology of Cyperus rotundus

Cyperus rotundus (nut grass in English) is a perennial erect sedge plant and is distributed in over 90 countries of the world, where it has been mostly classified as a highly invasive weed. Despite this classification, the plant has been considered from traditional times to be medicinally important. The traditional uses of the plant in various countries include uses against various gastrointestinal tract disorders, skin diseases, leprosy, fever, and neurological disorders. Evaluation of the plant and especially its rhizomes in a scientific manner has revealed the presence of numerous phytochemicals and wide-ranging pharmacological activities, which include anti-microbial, gastrointestinal, wound healing, anti-diabetic, anti-cancer, anti-malarial, anti-obesity, hepatoprotective, and anti-pyretic activity. The scientific validation of a number of traditional uses strongly indicates that the plant may prove useful in the discovery of a number of lead compounds and novel drugs.

Biomedical Applications of Nanoparticles

In recent years, there has been significant growth and burgeoning interest in utilizing nanoparticles for various biomedical applications, including medical diagnostics, targeted drug delivery, tissue engineering, regenerative medicine, and biomedical textiles. In particular, nanoparticles functionalized with biological molecules have unique properties and are very effective in medical diagnostics. Besides that, nanoparticles have a wide range of therapeutic applications, including the development of nanodrug delivery systems, the design of novel drugs, as well as their contribution to the design of therapeutic materials. This chapter provides an overview of recent advancements in the biomedical applications of nanoparticles. Finally, this chapter discusses the challenges of the toxicological evaluation of engineered nanoparticles and the importance of conducting detailed studies on the synthesis of future nanomaterials to develop cutting-edge technologies for addressing a wide range of biomedical issues.

Medicinal Plants

Medicines of plant origin have been used for treating humans and animals without any adverse effects. New medicinal plants are searched to develop more effective and cheaper drugs in place of synthetics drugs. Plants represent a large natural source of compounds that might serve for the development of novel drugs. Currently medicinal herbs are researched for diuretic properties, and several medicinal herbs are used as diuretics. Currently various synthetic medicines are available for this purpose; however, natural resource medicines are still an important choice because of their higher efficiency and better safety. Further, some herbs are also important sources of antioxidants, which protect the body from the effects of free radicals produced in the body. Antioxidants are required by our body due to increase in the likely exposure of the body to harmful pollutants, radiation, UV lights, etc. These have the ability to delay the oxidation, and plant-derived products are of great interest due to the adverse effect of antibiotics.

Plant-Derived Compounds and Their Potential Role in Drug Development

This article describes how with the development of biotechnology, plants have gained again a prominent place as a relatively inexpensive source for the creation of recombinant pharmaceuticals. Plant-derived compounds have started playing a major role in the pharmaceutical industry with many plant-based products to have found their way in drugs and chemicals used for the treatment of different diseases and their symptoms. Plant-derived compounds have been tested for the treatment of several types of cancer, Central Nervous System disorders, as enhancers during chemotherapy and as vessels for targeted drug delivery. Genetically modified plant cells have been recruited for the production of therapeutic agencies as well as in the creation of expression systems for virus-like particles that could be used as vaccines. Moreover, microRNAs mimicking the plant ones have the ability to inhibit tumors in mammalian cells. This review describes plant-derived compounds and their properties as potential therapeutic agents and precursors for the development of novel drugs in the pharmaceutical industry.

Glycosides for Peripheral Neuropathic Pain: A Potential Medicinal Components

Neuropathic pain is a refractory disease that occurs across the world and pharmacotherapy has limited efficacy and/or safety. This disease imposes a significant burden on both the somatic and mental health of patients; indeed, some patients have referred to neuropathic pain as being ‘worse than death’. The pharmacological agents that are used to treat neuropathic pain at present can produce mild effects in certain patients, and induce many adverse reactions, such as sedation, dizziness, vomiting, and peripheral oedema. Therefore, there is an urgent need to discover novel drugs that are safer and more effective. Natural compounds from medical plants have become potential sources of analgesics, and evidence has shown that glycosides alleviated neuropathic pain via regulating oxidative stress, transcriptional regulation, ion channels, membrane receptors and so on. In this review, we summarize the epidemiology of neuropathic pain and the existing therapeutic drugs used for disease prevention and treatment. We also demonstrate how glycosides exhibit an antinociceptive effect on neuropathic pain in laboratory research and describe the antinociceptive mechanisms involved to facilitate the discovery of new drugs to improve the quality of life of patients experiencing neuropathic pain.

Analysis of novel antineoplastic drugs treatment impact on the federal project «cancer control» goals achievement

The Federal project “Cancer Control” was launched in 2019. Its main objective is to reduce mortality from malignant neoplasms in Russia. The main goal of this research is to develop a methodology for assessment of innovative drugs treatment impact on reducing mortality from neoplasms (including malignant) and testing it in the case of some novel drugs. Materials and methods. Firstly, we assessed the number of patients, who annually can start a novel drug treatment. Afterwards we estimated the number of deaths, which could be avoided due to the efficacy differences between innovative drugs compared to the standard of care in terms of overall survival. Obtained results were than correlated to the reduction in malignant mortality ratio needed to achieve annually (comparing to the basis 2020). For the approbation of the model, we chose durvalumab, osimertinib and olaparib, which are indicated for lung and ovarian cancer treatment. Results. Annually 6 746 patients can start the treatment: 2 391 with durvalumab, 2 334 with osimertinib, 2 021 with olaparib. In the 2021-2023 frame durvalumab treatment can help to avoid 779 deaths, osimertinib treatment can help to avoid 723 deaths, olaparib treatment can help to avoid 679 deaths (totally 10,8% of reduction in deaths needed to achieve 2021-2023 goals). Conclusion. Novel antineoplastic drugs treatment leads to a quantifiable reduction in mortality from malignant neoplasms in Russia.