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Metabolic syndrome (MS) has a high prevalence, with an estimated one-quarter of the world population affected by this pathological condition. Among the diseases of this syndrome are dysregulation of lipids, hypertension, and insulin resistance. Unfortunately, available drugs in the market used for treating MS, as almost 75% of all drugs, are highly insoluble, presenting a significant demand for strategies to increase their solubility. Taking advantage of the fact that drugs in the amorphous state can provide a solubility enhancement, a new drug-drug co-amorphous (CoA) formulation to potentially simultaneously treat two or more MS conditions was explored, combining the co-formers Bezafibrate (BZT) a lipid-regulating drug, and Gliclazide (GZD) a hypoglycemic agent. A phase diagram was constructed to characterize the binary system's thermal properties, including glass transition temperatures of all compositions studied. The formulations were characterized by FTIR; redshifts of IR bands from 1547 to 1538 cm–1 and 1717 to 1609 cm–1 were observed due to the formation of intermolecular interactions, such as hydrogen bonds. The co-amorphous binary systems lead to an increase in the solubility of both BZT and GZD; specifically, for the composition xBZT = 0.5, the increase was 2.1× for BZT and 1.5 times for GZD while for xBZT = 0.7 an increase of 4× of BZT was achieved. The structural stability of the samples was verified by XRD and DSC, showing long-term stability retention of the amorphous state for more than eight years. The enhanced solubility and stability of the co-amorphous systems make them potential formulations for regulating lipids and lowering glycemia. [ABSTRACT FROM AUTHOR]

Introduction/Aim. Understanding the mechanisms and classification of drug interactions can significantly reduce the occurrence of adverse effects and improve compliance. The drug selection process is complex and involves the patient's individual condition, physiological status, use of other drugs, and co-existing illnesses. It is particularly challenging to choose adequate therapy for elderly individuals due to physiological changes and polypharmacy. The aim of this paper is to highlight the importance of an individualized approach to each patient when interpreting information provided by the existing drug databases. This approach involves considering the patient's age, comorbidities, and a proper assessment of the risk-benefit ratio. Methods. A comparative analysis of potential drug-drug interactions was conducted on a sample of 215 outpatients. The analysis was performed using Lexicomp®, Medscape® and Epocrates® databases. The frequency of certain types of interactions by drug databases, the number of patients, and the distribution of interaction types by databases were determined. The frequency of drug combinations that could potentially cause serious and contraindicated interactions by databases were also determined. Results. Based on the study, it can be concluded that there is a correlation between the number of prescribed drugs and potential interactions. According to frequency, the most common type of interaction requires therapy monitoring (type C interaction, Monitor). However, based on the severity categorization, the same drug combinations have different classifications of interactions in available databases. Conclusion. The obtained data can provide guidance in making decisions about drug therapy choices. Patient-specific characteristics, including comorbidities, require a personalized therapeutic approach from specialists, where pharmacists play a significant role. [ABSTRACT FROM AUTHOR]

In a typical tablet or capsule formulation, the active drug is often present as a crystalline solid. This solid emerges from the relationships between the individual atoms within the crystal, which confer a distinct set of physical properties. Then, it follows that if we modify the packing arrangement of the individual molecules within these crystals, we can modulate their properties. This can be achieved by crystal engineering. Crystal engineering has also seen teams arrange multiple drug molecules within the same crystal, resulting in dramatic improvements to drug properties in the lab. The success of drugs like SEGLENTIS® and Entresto® have revitalised interest in these forms, but controversy surrounding their translation has prompted this reconsideration of their clinical utility. I reflect on the current academic, clinical, and commercial interest in multidrug multicomponent crystals, drawing parallels with developments pre-Bragg, contributing to a nuanced understanding of the potential and limitations of crystal engineering in pharmaceutical applications. [Display omitted] • Blockbuster medicines has initiated a growing interest in these forms. • A growing number of literature reports postulate novel clinical impacts. • No author has demonstrated the superiority of their novel form. • Unusual clinical trial methods for Entresto® and now SEGLENTIS® are highlighted. [ABSTRACT FROM AUTHOR]

Abstract: Flubendazole (FLU), a benzimidazole anthelmintic drug widely used in veterinary medicine, has been approved for the treatment of gut‐residing nematodes in humans. In addition, FLU is now considered a promising anti‐cancer agent. Despite this, information about biotransformation of this compound in human is lacking. Moreover, there is no information regarding whether cancer cells are able to metabolize FLU in order to deactivate it. For these reasons, the present study was designed to identify all metabolites of Phase I and Phase II of FLU in human liver and in various cancer cells using ultra high‐performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) analysis. Precision‐cut human liver slices and 9 cell lines of different origin (breast, colon, oral cavity) were used as in vitro model systems. Our study showed that FLU with a reduced carbonyl group (FLUR) is the only FLU metabolite formed in the human liver. All human cancer cell lines were able to form FLUR. In addition, methylated FLUR was detected in breast cells MCF7 and intestinal SW480 cells. The accumulation of FLU and its reduction to FLUR markedly differed among cells. The extent of FLU reduction was in a good correlation with the detected expression level of carbonyl reductase 1. In most cases, FLU entered in a higher amount and was reduced to a lesser extent in proliferating (metastatic) cells than in differentiated (non‐cancerous, non‐metastatic) ones. These results support the promising potential of FLU in anti‐cancer therapy. [ABSTRACT FROM AUTHOR]

Purpose To assess whether a 'drugome-wide' screen with case-crossover design is a feasible approach for identifying candidate drugs and drug-drug interactions. Methods All community-dwelling residents of Finland who received a clinically verified Alzheimer disease diagnosis in 2005 to 2011 and experienced incident hip fracture (HF) afterwards (N = 4851). Three scenarios were used to test the sensitivity of this approach (1) hazard period 0 to 30 and control period 31 to 61 days before HF, (2) hazard period 0 to 30 and control period 336 to 366 days before HF, and (3) hazard period 0 to 14 and control period 16 to 30 days before HF. Results Nine, 44, and 5 drugs were associated with increased HF risk and 8, 23, and 4 with decreased risk in scenarios 1, 2, and 3, respectively. Six drugs were identified with scenario 1 only and 54 and 1 with scenarios 2 and 3, respectively. Only six drugs (metoprolol, simvastatin, trimethoprim, codeine combinations, fentanyl, and paracetamol) were associated with HF in all scenarios, four with 1 and 2 (cefalexin, buprenorphine, olanzapine, and memantine), and one with 1 and 3 (enalapril) or 2 and 3 (ciprofloxacin). The direction of associations was the same in all/both scenarios. The interaction results were equally versatile, with hydroxocobalamin*oxazepam being the only interaction observed in all scenarios. Conclusions Case-crossover analysis is a potential approach for identifying candidate drugs and drug-drug interactions associated with adverse events as it implicitly controls for fixed confounders. The results are highly dependent on applied hazard and control periods, but the choice of periods can help in targeting the analyses to different phases of drug use. [ABSTRACT FROM AUTHOR]

1. Among the differentin vitrostudies recommended by the regulatory agencies, no gold-standard model can easily and directly measure the quantitative CYP450 contributions to drug biotransformation. In this article, we propose an original strategy, called SilensomesTM, to produce human liver microsomes silenced for one specific CYP450, thanks to specific mechanism-based inhibitors (MBI). 2. Using azamulin as a specific CYP3A4 MBI, we demonstrated the proof of concept that CYP3A4 can be totally, specifically (even against 3A5) and permanently (at least for six years) inhibited by our process. Thus, comparing clearance in control and CYP3A4-SilensomesTM, CYP3A4 contributions were determined for 11 CYP3A4 substrates which correlated with knownin vivocontributions and revealed accuracy with less than 10% error. In comparison, contributions determined using recombinant human CYP450 (rhCYP450s) were less accurate (more than 10% error for 30% of the tested CYP3A4 substrates). 3. This easy and ready-to-use in vitro method combines the advantages of existing models (specificity of rhCYP450s and representativeness of HLM) without their drawbacks. The same strategy could be used to silence other major CYP450s one-by-one to provide a complete direct CYP450 quantitative phenotyping kit. [ABSTRACT FROM AUTHOR]

There are many factors that can affect the pharmacokinetics (PK) of drugs. Pathophysiological changes from disease states can alter the mechanisms that control the PK of antiretrovirals (ARVs), direct-acting antivirals (DAAs), and addiction treatment medications. Drug-drug interaction pathways of certain ARVs and DAAs can be very complex, with agents being substrates, inhibitors, or inducers of multiple metabolic and transporter pathways. Buprenorphine and methadone may be used in HIV- and hepatitis C virus (HCV)-infected patients and may also be affected by drug interactions. Current research is focused on novel PK analyses, which aim to describe the PK of agents within organs that host the infection of interest, such as within hepatocytes during treatment for HCV. Modeling techniques allow for the prediction of drug PK in specific organs and the plasma compartment. This review will provide a summary of these areas while exploring PK considerations for ARVs, DAAs, and addiction treatment medications. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study aims to analyze pharmacological interactions among drugs taken by elderly patients and their age and gender differences in a population from Porto Alegre, Brazil. METHODS: We retrospectively analyzed the database provided by the Institute of Geriatric and Gerontology, Porto Alegre, Brazil. The database was composed of 438 elderly and includes information about the patients' disease, therapy regimens, utilized drugs. All drugs reported by the elderly patients were classified using the Anatomical Therapeutic and Chemical Classification System. The drug-drug interactions and their severity were assessed using the Micromedex® Healthcare Series. RESULTS: Of the 438 elderly patients in the data base, 376 (85.8%) used pharmacotherapy, 274 were female, and 90.4% of females used drugs. The average number of drugs used by each individual younger than 80 years was 3.2±2.6. Women younger than 80 years old used more drugs than men in the same age group whereas men older than 80 years increased their use of drugs in relation to other age groups. Therefore, 32.6% of men and 49.2% of women described at least one interaction, and 8.1% of men and 10.6% of women described four or more potential drug-drug interactions. Two-thirds of drug-drug interactions were moderate in both genders, and most of them involved angiotensin-converting enzyme inhibitor, non-steroidal anti-inflammatory, loop and thiazide diuretics, and β-blockers. CONCLUSION: Elderly patients should be closely monitored, based on drug class, gender, age group and nutritional status.

Cardiovascular disease is the leading cause of morbidity in the adult Venezuelan population, leading to a significant number of hospitalized patients receiving combination therapy, which may cause drug interactions (IF). The aim of this study was to evaluate potential IF polypharmacy in patients with cardiovascular disease. This was an observational, descriptive cross-sectional study; medical records of 87 hospitalized patients were reviewed with a stage of three days or more. The data collection form recorded: history number, age, gender, admission and discharge dates, type of cardiovascular disease; administered drugs, treatment start and completion dates. Identification of potential IF was performed using the TOX MED program. Results showed an average age of 63.82; predominantly males and potential association between IF and prescription of more than seven drugs (p = 0.002). The most frequent diseases were acute coronary syndrome and hypertension; antithrombotic agents were the most commonly prescribed drugs. 519 IF potential were identified; pharmacokinetic 51 (30.32%) and pharmacodynamic 347 (69.68%), the most frequent ones being metabolism (84.79%) and synergism (75.79%), respectively. The highest percentage of potential pharmacokinetic IF was associated with atorvastatin - clopidogrel (22.52%), and pharmacodynamic with aspirin - heparin (15.71%). It is concluded that the number of pharmacokinetic or pharmacodynamic IF potential increases with the number of drugs that patients take.. [ABSTRACT FROM AUTHOR]

Multidrug and toxin extrusion proteins (MATEs; SLC47A) are mammalian transporters being predominately expressed in the brush-border membrane of proximal tubule epithelial cells in the kidney and the canalicular membrane of hepatocytes. Functionally, MATEs act as efflux transporters for organic compounds, thereby mediating the elimination process. Two isoforms, MATE1 and 2, have been identified, and, so far, only a limited number of substrates, including clinically used drugs such as metformin and cimetidine, are known. A knockout mouse model has been established, as well, and is a valuable tool for further systematic pharmacokinetic analyses. In this review, we summarize the progress in MATE research on structural, molecular, functional, and pathophysiological aspects. Consequences of genetic variants for pharmacokinetic alterations and drug therapy are discussed. [ABSTRACT FROM AUTHOR]

Background: The proteasome inhibitor bortezomib undergoes oxidative biotransformation via multiple cytochrome P450 (CYP) enzymes, with CYP3A4 identified as a partial, yet potentially important, contributor based on in vitro drug metabolism studies. Objective: The aim of this study was to assess the effect of concomitant administration of ketoconazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib. Methods: This was a prospective, multicenter, openlabel, randomized, multiple-dose, 2-way crossover study in patients with advanced solid tumors. All patients received bortezomib 1.0 mg/m2 IV (on days 1, 4, 8, and 11 of two 21-day cycles) and were randomized to receive concomitant ketoconazole 400 mg on days 6, 7, 8, and 9 of cycle 1 or 2. Serial blood samples were collected over the day-8 dosing interval (immediately prior to bortezomib administration, and from 5 minutes to 72 hours after administration) in cycles 1 and 2 for measurement of plasma bortezomib concentrations for noncompartmental PK analysis and blood 20S proteasome inhibition for PD analysis. All adverse events (AEs) were recorded during each cycle including serious AEs and all neurotoxicity events for up to 30 days after the last dose of bortezomib. Results: Twenty-one patients (median age, 57 years; sex, 67% male; race, 86% white; median body surface area, 2.01 m2) were randomized to treatment. Twelve pa- tients completed the protocol-specified dosing and PK sampling in both cycles 1 and 2. Assessment of the effect of ketoconazole on bortezomib PK and PD was based on data in these 12 PK-evaluable patients. The ratio of geometric mean bortezomib AUC0-tlast(AUC from time 0 to last quantifiable concentration) for bortezomib plus ketoconazole versus bortezomib alone was 1.352 (90% CI, 1.032–1.772). Consistent with this observed mean increase in bortezomib exposure, concomitant administration of ketoconazole was associated with a corresponding increase (24%–46%) in the blood proteasome inhibitory effect. Conclusion: Concomitant administration of the CYP3A inhibitor ketoconazole with bortezomib resulted in a mean increase of 35% in bortezomib exposure. ClinicalTrials.gov identifier: NCT00129207. [Copyright &y& Elsevier]

Abstract: Background: Although many potential drug-drug interactions (DDIs) are discussed in the clinical literature, only limited numbers of these are clinically important. Little is known about prescribing of agents involved in these clinically important DDIs at the national level. Objective: This study examined concomitant prescribing of drug combinations that have potential for clinically important DDIs in outpatient settings in the United States. Methods: The 2000-2002 National Ambulatory Medical Care Survey and the outpatient department portion of the 2000-2002 National Hospital Ambulatory Medical Care Survey were used to examine 25 clinically important DDIs that are most likely to harm patients if not detected. Descriptive statistics were used to characterize clinically important DDIs, whereas logistic regression analysis was applied to outpatient visits to examine patients at risk for clinically important DDIs. Results: An estimated 0.63% (95% confidence interval, 0.51-0.75) of outpatient visits involving 2 or more medications resulted in prescription combinations with potential for clinically important DDIs for an annual visit estimate of 2.26 million, or annual visit rate of 8.12 visits per 1000 persons. Fourteen of the 25 prescription combinations with potential for clinically important DDIs were prescribed in outpatient settings, with warfarin accounting for many of the visits that yielded the prescribing of interacting medications. A majority (82%) of the prescriptions for potentially interacting medications occurred in visits involving 5 or more medications. The study found that patients over 44 years of age, especially elderly, Medicare beneficiaries, and those prescribed multiple medications are at risk for receiving prescription combinations with potential for a clinically important DDI. Conclusions: Although a small percentage of outpatient visits resulted in prescription combinations with potential for clinically important DDIs, these interactions can have significant implications due to medication-related morbidity and mortality. Pharmacists can play a critical role in managing the medication therapy of patients at risk for clinically important DDIs. Further research is needed to evaluate the economic, clinical, and humanistic outcomes of clinically important DDIs, especially among those at risk. [Copyright &y& Elsevier]

Massive data available on cancer therapy more than ever lead our mind to the general concept that there is no perfect treatment for cancer. Indeed, the biological complexity of this disease is too excessive to be treated by a single therapeutic approach. Current delivery systems containing a specific drug or gene have their particular opportunities and restrictions. It is worth noting that a considerable number of studies suggest that single- drug delivery systems result in insufficient suppression of cancer growth. Therefore, one of the main ideas of co-delivery system designing is to enhance the intended response or to achieve the synergistic/combined effect compared to the single drug strategy. This review focuses on various strategies for co-delivery of therapeutic agents in the treatment of cancer. The primary approaches within the script are categorized into co-delivery of conventional chemotherapeutics, gene-based molecules, and plant-derived materials. Each one is explained in examples with the recent researches. In the end, a brief summary is provided to conclude the gist of the review., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Flubendazole (FLU), a benzimidazole anthelmintic drug widely used in veterinary medicine, has been approved for the treatment of gut-residing nematodes in humans. In addition, FLU is now considered a promising anti-cancer agent. Despite this, information about biotransformation of this compound in human is lacking. Moreover, there is no information regarding whether cancer cells are able to metabolize FLU in order to deactivate it. For these reasons, the present study was designed to identify all metabolites of Phase I and Phase II of FLU in human liver and in various cancer cells using ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis. Precision-cut human liver slices and 9 cell lines of different origin (breast, colon, oral cavity) were used as in vitro model systems. Our study showed that FLU with a reduced carbonyl group (FLUR) is the only FLU metabolite formed in the human liver. All human cancer cell lines were able to form FLUR. In addition, methylated FLUR was detected in breast cells MCF7 and intestinal SW480 cells. The accumulation of FLU and its reduction to FLUR markedly differed among cells. The extent of FLU reduction was in a good correlation with the detected expression level of carbonyl reductase 1. In most cases, FLU entered in a higher amount and was reduced to a lesser extent in proliferating (metastatic) cells than in differentiated (non-cancerous, non-metastatic) ones. These results support the promising potential of FLU in anti-cancer therapy., (Copyright © 2018 John Wiley & Sons, Ltd.)