Infections are a growing global threat, and the number of resistant species of microbial pathogens is alarming. However, the rapid development of cross-resistant or multidrug-resistant strains and the development of so-called 'superbugs' are in stark contrast to the number of newly launched anti-infectives on the market. In this review, I summarize the causes of antimicrobial resistance, briefly discuss different approaches to the discovery and development of new anti-infective drugs, and focus on drug repurposing strategy, which is discussed from all possible perspectives. A comprehensive overview of drugs of other indications tested for their in vitro antimicrobial activity to support existing anti-infective therapeutics is provided, including several critical remarks on this strategy of repurposing non-antibiotics to antibacterial drugs.

• Klíčová slova
• Antibiotics, Antimicrobial resistance, Drug repurposing, Infections, Non-antibiotic drugs,
• MeSH
• antibakteriální látky farmakologie   terapeutické užití   MeSH
• antiinfekční látky * MeSH
• přehodnocení terapeutických indikací léčivého přípravku * MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antibakteriální látky MeSH
• antiinfekční látky * MeSH

• Klíčová slova
• DMARDs (biologic), DMARDs (synthetic), Epidemiology,
• MeSH
• antirevmatika škodlivé účinky   MeSH
• biologické přípravky škodlivé účinky   MeSH
• lidé MeSH
• registrace normy   MeSH
• revmatické nemoci farmakoterapie   MeSH
• systémy pro sběr zpráv o nežádoucích účincích léků organizace a řízení   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• komentáře MeSH
• Názvy látek
• antirevmatika MeSH
• biologické přípravky MeSH

While it is true that only a small fraction of fungal species are responsible for human mycoses, the increasing prevalence of fungal diseases has highlighted an urgent need to develop new antifungal drugs, especially for systemic administration. This contribution focuses on the similarities between agricultural fungicides and drugs. Inorganic, organometallic and organic compounds can be found amongst agricultural fungicides. Furthermore, fungicides are designed and developed in a similar fashion to drugs based on similar rules and guidelines, with fungicides also having to meet similar criteria of lead-likeness and/or drug-likeness. Modern approved specific-target fungicides are well-characterized entities with a proposed structure-activity relationships hypothesis and a defined mode of action. Extensive toxicological evaluation, including mammalian toxicology assays, is performed during the whole discovery and development process. Thus modern agrochemical research (design of modern agrochemicals) comes close to drug design, discovery and development. Therefore, modern specific-target fungicides represent excellent lead-like structures/models for novel drug design and development.

• Klíčová slova
• agricultural fungicides, antifungal drugs, drug design and discovery, drug-likeness, lead-likeness, mycoses,
• MeSH
• agrochemikálie chemie   farmakologie   MeSH
• antifungální látky chemie   farmakologie   MeSH
• fungicidy průmyslové chemie   farmakologie   MeSH
• houby účinky léků   MeSH
• lidé MeSH
• mykózy farmakoterapie   MeSH
• objevování léků metody   MeSH
• racionální návrh léčiv MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• úvodníky MeSH
• Názvy látek
• agrochemikálie MeSH
• antifungální látky MeSH
• fungicidy průmyslové MeSH

Antibiotics are considered to be one of the most important discoveries of medicine, which has significantly affected the mortality due to infectious diseases. Given their increasing use, certain problems arise over time, resulting from non-indicated and inadequate - administration of antibiotics. This results in increasing antibiotic resistance as well as a higher risk of side/adverse effects. Recently, these side effects of drugs have been used for indications other than those originally intended and approved. Such a process is called drug repositioning. Due to the recent increase in the cost of developing novel drugs and the high risk of failure in clinical trials, the pharmaceutical industry is trying to find new indications for existing drugs.

• MeSH
• antibakteriální látky škodlivé účinky   MeSH
• cytostatické látky * MeSH
• farmaceutický průmysl MeSH
• lidé MeSH
• nežádoucí účinky léčiv * MeSH
• přehodnocení terapeutických indikací léčivého přípravku MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• cytostatické látky * MeSH

• Klíčová slova
• AGRANULOCYTOSIS *, DRUG ALLERGY *, HEMATOLOGY *, THROMBOPENIA *,
• MeSH
• agranulocytóza * MeSH
• hematologie * MeSH
• léková alergie * MeSH
• lidé MeSH
• trombocytopenie * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND AND OBJECTIVE: In silico prediction of drug-target interactions (DTI) could provide valuable information and speed-up the process of drug repositioning - finding novel usage for existing drugs. In our work, we focus on machine learning algorithms supporting drug-centric repositioning approach, which aims to find novel usage for existing or abandoned drugs. We aim at proposing a per-drug ranking-based method, which reflects the needs of drug-centric repositioning research better than conventional drug-target prediction approaches. METHODS: We propose Bayesian Ranking Prediction of Drug-Target Interactions (BRDTI). The method is based on Bayesian Personalized Ranking matrix factorization (BPR) which has been shown to be an excellent approach for various preference learning tasks, however, it has not been used for DTI prediction previously. In order to successfully deal with DTI challenges, we extended BPR by proposing: (i) the incorporation of target bias, (ii) a technique to handle new drugs and (iii) content alignment to take structural similarities of drugs and targets into account. RESULTS: Evaluation on five benchmark datasets shows that BRDTI outperforms several state-of-the-art approaches in terms of per-drug nDCG and AUC. BRDTI results w.r.t. nDCG are 0.929, 0.953, 0.948, 0.897 and 0.690 for G-Protein Coupled Receptors (GPCR), Ion Channels (IC), Nuclear Receptors (NR), Enzymes (E) and Kinase (K) datasets respectively. Additionally, BRDTI significantly outperformed other methods (BLM-NII, WNN-GIP, NetLapRLS and CMF) w.r.t. nDCG in 17 out of 20 cases. Furthermore, BRDTI was also shown to be able to predict novel drug-target interactions not contained in the original datasets. The average recall at top-10 predicted targets for each drug was 0.762, 0.560, 1.000 and 0.404 for GPCR, IC, NR, and E datasets respectively. CONCLUSIONS: Based on the evaluation, we can conclude that BRDTI is an appropriate choice for researchers looking for an in silico DTI prediction technique to be used in drug-centric repositioning scenarios. BRDTI Software and supplementary materials are available online at www.ksi.mff.cuni.cz/∼peska/BRDTI.

• Klíčová slova
• Bayesian personalized ranking, Drug repositioning, Drug-target interactions, Machine learning,
• MeSH
• algoritmy MeSH
• Bayesova věta * MeSH
• datové soubory jako téma MeSH
• farmakologie * MeSH
• lidé MeSH
• přehodnocení terapeutických indikací léčivého přípravku MeSH
• strojové učení MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• PHARMACOLOGY *,
• MeSH
• farmakologie * MeSH
• kontrola léčiv a omamných látek * MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Pharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both. The knowledge of drug transport across placenta is, therefore, an important topic to bear in mind when deciding treatment in pregnant women. Several drug transporters of the ABC and SLC families have been discovered in the placenta, such as P-glycoprotein, breast cancer resistance protein, or organic anion/cation transporters. It is thus evident that the passage of drugs across the placenta can no longer be predicted simply on the basis of their physical-chemical properties. Functional expression of placental drug transporters in the trophoblast and the possibility of drug-drug interactions must be considered to optimize pharmacotherapy during pregnancy. In this review we summarize current knowledge on the expression and function of ABC and SLC transporters in the trophoblast. Furthermore, we put this data into context with medical conditions that require maternal and/or fetal treatment during pregnancy, such as gestational diabetes, HIV infection, fetal arrhythmias and epilepsy. Proper understanding of the role of placental transporters should be of great interest not only to clinicians but also to pharmaceutical industry for future drug design and development to control the degree of fetal exposure.

• MeSH
• ABC transportéry metabolismus   MeSH
• biologický transport MeSH
• komplikace těhotenství farmakoterapie   patofyziologie   MeSH
• léčivé přípravky aplikace a dávkování   metabolismus   MeSH
• lékové interakce MeSH
• lidé MeSH
• maternofetální výměna látek fyziologie   MeSH
• membránové transportní proteiny metabolismus   MeSH
• placenta metabolismus   MeSH
• racionální návrh léčiv MeSH
• těhotenství MeSH
• trofoblasty metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• ABC transportéry MeSH
• léčivé přípravky MeSH
• membránové transportní proteiny MeSH

BACKGROUND: The study aimed to evaluate the agreement of prescribed drug dosages with renal dosing recommendations and describe adverse drug events (ADEs) contributing to hospital admissions of patients with chronic kidney disease (CKD). METHODS: This cross-sectional study focused on CKD patients admitted to University Hospital Hradec Králové, with an estimated glomerular filtration rate below 60 ml/min. The necessity for renal dosage adjustments was determined using the Summary of Product Characteristics (SmPC). For medications requiring renal dosage adjustment according to SmPC, agreement between the prescribed and recommended renal dosage was assessed. ADEs were adjudicated using the OPERAM drug-related hospital admissions adjudication guide. RESULTS: Of 375 CKD patients, 112 (30%, 95% CI 25-34) were prescribed drug dosages in disagreement with SmPC renal dosage recommendations. Perindopril, metformin, and ramipril were most frequently dosed in disagreement with SmPC. ADE-related hospital admissions occurred in 20% (95% CI 16-24) of CKD patients. CONCLUSION: CKD patients are often prescribed medication dosages in disagreement with SmPC renal dosing recommendations. Besides explicit factors, treatment goals, feasibility of monitoring and alternative treatment must be weighed when assessing drug and dosage appropriateness. Gastrointestinal bleeding was the most frequent ADE that contributed to hospital admissions of CKD patients.

• Klíčová slova
• Adverse drug event, adverse drug reaction, chronic kidney disease, hospitalization, medication error,
• MeSH
• chronická renální insuficience * komplikace   MeSH
• hodnoty glomerulární filtrace MeSH
• ledviny MeSH
• lidé MeSH
• nemocnice MeSH
• nežádoucí účinky léčiv * epidemiologie   etiologie   MeSH
• průřezové studie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.

• Klíčová slova
• Neuroblastoma, clinical trials, drug development, phase I, preclinical testing,
• MeSH
• antitumorózní látky škodlivé účinky   farmakologie   MeSH
• časové faktory MeSH
• cílená molekulární terapie MeSH
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• neuroblastom farmakoterapie   patologie   MeSH
• preklinické hodnocení léčiv metody   MeSH
• prognóza MeSH
• racionální návrh léčiv * MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky MeSH