The Overview on the Pharmacokinetic and Pharmacodynamic Interactions of Triazoles

Second generation triazoles are widely used as first-line drugs for the treatment of invasive fungal infections, including aspergillosis and candidiasis. This class, along with itraconazole, voriconazole, posaconazole, and isavuconazole, is characterized by a broad range of activity, however, individual drugs vary considerably in safety, tolerability, pharmacokinetics profiles, and interactions with concomitant medications. The interaction may be encountered on the absorption, distribution, metabolism, and elimination (ADME) step. All triazoles as inhibitors or substrates of CYP isoenzymes can often interact with many drugs, which may result in the change of the activity of the drug and cause serious side effects. Drugs of this class should be used with caution with other agents, and an understanding of their pharmacokinetic profile, safety, and drug-drug interaction profiles is important to provide effective antifungal therapy. The manuscript reviews significant drug interactions of azoles with other medications, as well as with food. The PubMed and Google Scholar bases were searched to collect the literature data. The interactions with anticonvulsants, antibiotics, statins, kinase inhibitors, proton pump inhibitors, non-nucleoside reverse transcriptase inhibitors, opioid analgesics, benzodiazepines, cardiac glycosides, nonsteroidal anti-inflammatory drugs, immunosuppressants, antipsychotics, corticosteroids, biguanides, and anticoagulants are presented. We also paid attention to possible interactions with drugs during experimental therapies for the treatment of COVID-19.

Prevalence of potentially harmful multidrug interactions on medication lists of elderly ambulatory patients

Background It has been hypothesized that polypharmacy may increase the frequency of multidrug interactions (MDIs) where one drug interacts with two or more other drugs, amplifying the risk of associated adverse drug events (ADEs). The main objective of this study was to determine the prevalence of MDIs in medication lists of elderly ambulatory patients and to identify the medications most commonly involved in MDIs that amplify the risk of ADEs. Methods Medication lists stored in the electronic health record (EHR) of 6,545 outpatients ≥60 years old were extracted from the enterprise data warehouse. Network analysis identified patients with three or more interacting medications from their medication lists. Potentially harmful interactions were identified from the enterprise drug-drug interaction alerting system. MDIs were considered to amplify the risk if interactions could increase the probability of ADEs. Results MDIs were identified in 1.3 % of the medication lists, the majority of which involved three interacting drugs (75.6 %) while the remainder involved four (15.6 %) or five or more (8.9 %) interacting drugs. The average number of medications on the lists was 3.1 ± 2.3 in patients with no drug interactions and 8.6 ± 3.4 in patients with MDIs. The prevalence of MDIs on medication lists was greater than 10 % in patients prescribed bupropion, tramadol, trazodone, cyclobenzaprine, fluoxetine, ondansetron, or quetiapine and greater than 20 % in patients prescribed amiodarone or methotrexate. All MDIs were potentially risk-amplifying due to pharmacodynamic interactions, where three or more medications were associated with the same ADE, or pharmacokinetic, where two or more drugs reduced the metabolism of a third drug. The most common drugs involved in MDIs were psychotropic, comprising 35.1 % of all drugs involved. The most common serious potential ADEs associated with the interactions were serotonin syndrome, seizures, prolonged QT interval and bleeding. Conclusions An identifiable number of medications, the majority of which are psychotropic, may be involved in MDIs in elderly ambulatory patients which may amplify the risk of serious ADEs. To mitigate the risk, providers will need to pay special attention to the overlapping drug-drug interactions which result in MDIs.

Herb-drug interactions in neuropsychiatric pharmacotherapy – a review of clinically relevant findings

: The management of neuropsychiatric disorders relies heavily on pharmacotherapy. The use of herbal products as complimentary medicine, often concomitantly, is common among patients taking prescription neuropsychiatric drugs. Herb-drug interaction, a clinical consequence of this practice, may jeopardize the success of pharmacotherapy in neuropsychiatry. Besides the well-known ability of phytochemicals to inhibit and/or induce drug-metabolizing enzymes and transport proteins, several phytoconstituents are capable of exerting pharmacological effects on the central nervous system. The consequent pharmacokinetic and pharmacodynamic interactions with orthodox medications often result in deleterious clinical consequences. This study reviewed the relevant literature and identified 13 commonly used herbal products – celery, echinacea, ginkgo, ginseng, hydroxycut, kava, kratom, moringa, piperine, rhodiola, St John’s wort, terminalia/commiphora ayurvedic mixture and valerian – which have shown clinically relevant interactions with prescription drugs used in the management of neuropsychiatric disorders. The clinical focus is aimed to provide easily accessible information that will be of interest to clinicians, researchers, and the drug-consuming public.

Assessment of Interactions of Drugs Prescribed for Pediatric Patients in Bangladesh

Drug-drug interactions (DDIs) represent an important clinical problem. During inpatient admissions, infants, children, and adolescents are typically exposed to different medications, increasing their risk of potential drug-drug interactions (pDDIs). While drug interactions are reported to be common, there are only few publications of the prevalence of such interactions among pediatric patients in Bangladesh. The present study tries to estimates the prevalence and characteristics of pDDI exposure of pediatric patients treated in children’s hospitals. This observational retrospective study was carried out on 155 patients admitted to a children’s hospital located at Dhaka during January 2019 to August 2019. The medications of the patients were analyzed for pDDIs by using Medscape drug interaction checker. The prescriptions were analyzed for demographic characteristics, medical and detailed drug history. Drug-drug interactions (DDIs) were evaluated for total numbers, types and severity of DDIs. Total 155 prescriptions with mean age 2.12±2.08 years were analyzed and a total of 25 pDDIs were recorded. The prevalence of pDDI was 17%, of which 12 (48%) were pharmacodynamic interactions, 10 (40%) were pharmacokinetic interactions and 3 (12%) of unknown mechanism. According to the severity of interaction, 4 (18%) cases were categorized as serious, 15 (55%) cases as moderate and 6 (27%) cases as minor. The occurrence of DDIs were significantly associated (r=0.912, p<0.05) with the number of drugs prescribed. The present study has identified pDDIs and also documented interactions in pediatrics patients. It has highlighted the need for screening prescriptions of pediatric patients for pDDIs and proactive monitoring of patients who have identified risk factors in order to promote detection and prevention of possible adverse drug interactions. Bangladesh Pharmaceutical Journal 24(2): 91-98, 2021

A randomized trial of safety and pharmacodynamic interactions between a selective glucocorticoid receptor antagonist, PT150, and ethanol in healthy volunteers

PT150, a novel competitive glucocorticoid receptor (GR) antagonist, has proven safe in animal models, healthy volunteers, and people with depression. Our study is the first to investigate PT150’s safety with alcohol use. The primary objective of this study was to evaluate pharmacodynamic interactions between ethanol and PT150 in healthy subjects. This single-site, Phase I pilot trial consisted of community-recruited, healthy, alcohol-experienced participants aged 21–64 years. Of 32 participants screened, 11 were enrolled and randomized, one of which withdrew before intervention. PT150 (900 mg/day) was administered orally to all participants for five days. All participants received two beverage challenges on Day 1 (before PT150 administration) and Day 5 (after PT150 administration). On challenge days, they received both alcohol (16% ethanol) and placebo (1% ethanol) beverages in random order. Primary outcomes included breath alcohol level, blood pressure, heart rate, adverse events, and electrocardiogram changes. There were no statistically significant differences in vital signs or estimated blood alcohol concentrations between PT150 non-exposed and exposed groups during the ethanol challenge. There were no clinically significant abnormal electrocardiograms or serious adverse events. These data show that administration of PT150 with concurrent alcohol use is safe and well-tolerated. This study supports a future pharmacokinetic interaction study between PT150 and alcohol.Trial Registration ClinicalTrials.gov Identifier: NCT03548714.

Topical issues of interaction of psychotropic drugs

In mental patients with concomitant somatic pathology, psychotropic drugs are prescribed in combination with other drugs used in the treatment of various somatic diseases. As well as a large number of patients with somatic diseases, they receive therapy aimed at correcting mental disorders. At the same time, it is important to take into account the possibility of cross-influence of such pharmacotherapy on the functions of the central nervous system and internal organs, as well as the peculiarities of drug interactions between drugs. According to the mechanism of development, there are pharmaceutical, pharmacokinetic and pharmacodynamic interactions of drugs. The result of the interaction of drugs is more often a change in the intensity of the effect of drugs, less often there are qualitative changes in their action. The review article provides up-to-date practical information on the interaction of drugs for the treatment of mental disorders with drugs of other groups.

Synergism and Subadditivity of Verbascoside-Lignans and -Iridoids Binary Mixtures Isolated from Castilleja tenuiflora Benth. on NF-κB/AP-1 Inhibition Activity

Pharmacodynamic interactions between plant isolated compounds are important to understand the mode of action of an herbal extract to formulate or create better standardized extracts, phytomedicines, or phytopharmaceuticals. In this work, we propose binary mixtures using a leader compound to found pharmacodynamic interactions in inhibition of the NF-κB/AP-1 pathway using RAW-Blue™ cells. Eight compounds were isolated from Castilleja tenuiflora, four were new furofuran-type lignans for the species magnolin, eudesmin, sesamin, and kobusin. Magnolin (60.97%) was the most effective lignan inhibiting the NF-κB/AP-1 pathway, followed by eudesmin (56.82%), tenuifloroside (52.91%), sesamin (52.63%), and kobusin (45.45%). Verbascoside, a major compound contained in wild C. tenuiflora showed an inhibitory effect on NF-κB/AP-1. This polyphenol was chosen as a leader compound for binary mixtures. Verbacoside-aucubin and verbascoside-kobusin produced synergism, while verbascoside-tenuifloroside had subadditivity in all concentrations. Verbascoside-kobusin is a promising mixture to use on NF-κB/AP-1 related diseases and anti-inflammatory C. tenuiflora-based phytomedicines.