The Interface between Cell Signaling Pathways and Pregnane X Receptor

Highly expressed in the enterohepatic system, pregnane X receptor (PXR, NR1I2) is a well-characterized nuclear receptor (NR) that regulates the expression of genes in the liver and intestines that encode key drug metabolizing enzymes and drug transporter proteins in mammals. The net effect of PXR activation is to increase metabolism and clear drugs and xenobiotics from the body, producing a protective effect and mediating clinically significant drug interaction in patients on combination therapy. The complete understanding of PXR biology is thus important for the development of safe and effective therapeutic strategies. Furthermore, PXR activation is now known to specifically transrepress the inflammatory- and nutrient-signaling pathways of gene expression, thereby providing a mechanism for linking these signaling pathways together with enzymatic drug biotransformation pathways in the liver and intestines. Recent research efforts highlight numerous post-translational modifications (PTMs) which significantly influence the biological function of PXR. However, this thrust of research is still in its infancy. In the context of gene-environment interactions, we present a review of the recent literature that implicates PXR PTMs in regulating its clinically relevant biology. We also provide a discussion of how these PTMs likely interface with each other to respond to extracellular cues to appropriately modify PXR activity.

Drug-related problems and associated factors in Ethiopia: a systematic review and meta-analysis

BackgroundDrug-related problems (DRPs) can occur at any stages of medication use processes, and a single drug could be associated with multiple DRPs. Once happened, it adversely affects health outcomes. In Ethiopia, evaluation of the magnitude and factors associated with DRPs had not been attempted at the national level.MethodThe literature search was conducted in the following databases; PubMed, Embase, Medline, and Google Scholar. The quality of the included studies was checked using Joanna Brigg’s Institute (JBI’s) checklist, and data were analyzed using Stata software (version 14.0). The pooled estimate of DRPs was computed by a Random effect model (DerSimonian–Laird method). Cochran’s Q test (I2) statistic)), and Begg’s correlation and Egger’s regression test were assessed for heterogeneity and publication bias, respectively.ResultOverall, 32 studies with a total sample size of 7,129 were included in the review. The estimated pooled prevalence of DRPs was 70% [0.70 (95% CI 0.64—0.76;I2 = 97.6%p = 0.000)]. Polypharmacy (taking ≥ 5 drugs) [RR = 1.3], medical comorbidity [RR = 1.3], poor medication adherence [RR = 1.7], uncontrolled blood pressure [RR = 1.4], substance use [RR = 1.2], type 2 diabetes [RR = 1.8], significant drug interaction [RR = 1.33], and a negative medication belief [RR = 3.72] significantly influenced the occurrence of DRPs.ConclusionThe estimated national prevalence of DRPs in Ethiopia was high.Presence of medical comorbidity, using multiple drugs, significant drug interaction, poor medication adherence, uncontrolled blood pressure, type 2 diabetes, substance use and a negative belief about medication significantly influenced the occurrence of DRPs. Initiating and/or strengthening pharmaceutical care services at the health care facilities could lower the occurrence of DRPs. PROSPERO registration number CRD42020162329.

Pharmacokinetic Drug Food Interaction Study of Nateglinide and Pomegranate Fruit Juice

Objective: Pomegranate juice is inhibitor of CYP450 enzyme system such as CYP2C9 and CYP3A4. The objective of the present study was to determine the consequence of pomegranate fruit juice on the pharmacokinetics of oral hypoglycemic drug nateglinide in rats. Materials and Methods: This is a laboratory study to investigate drug-food interaction effects of Punica granatum fruit juice (3 ml) and nateglinide (in doses 10 and 20 mg/kg body weight, p.o.) in live animals where the effects of food drug interaction on pharmacokinetics parameters such as Cmax and AUC in vehicle and nateglinide and pomegranate juice and nateglinide treated rats was undertaken. Four groups of Wistar albino rats comprising of (n=5) animals in each group were taken and treated with vehicle and nateglinide (in doses 10 and 20 mg/kg body weight, p.o.) pomegranate juice (3ml, p.o.) and nateglinide (in doses 10 and 20 mg/kg body weight, p.o.). Results: The rats which were administered with pomegranate juice + nateglinide (in doses 10 and 20 mg/kg body weight, p.o.) showed raised Cmax to 2.85 fold and 2.21-fold respectively and an increase in AUC was found to be 1.34 fold and 1.47 fold respectively, when vehicle + nateglinide 10mg/kg and vehicle + 20mg/kg drug treated groups were compared. The results were compared at P-value< 0.01. Conclusion: A significant drug interaction was observed when nateglinide and pomegranate juice was administered indicating caution must be exercised when such food and drug is co-administered as the chance of more hypoglycemia may occur due to this potential drug-food interaction.

Safety and efficacy of transitioning from the combination of bosentan and sildenafil to alternative therapy in patients with pulmonary arterial hypertension

The combination of bosentan and sildenafil is commonly used to treat patients with pulmonary arterial hypertension (PAH); however, there is evidence of a significant drug interaction between these two medications. We sought to evaluate the safety and efficacy of transitioning patients with PAH from the combination of bosentan and sildenafil to alternative therapy. A retrospective database review was performed on 16 patients with PAH who were treated with the combination of bosentan and sildenafil and transitioned to alternative treatment at our center. Invasive and non-invasive patient parameters were collected at baseline and after transition. 56.3% of patients were in World Health Organization functional class (WHO FC) III and a majority of patients (68.7%) were on background prostacyclin therapy. The most common reason for transition was concern for a drug interaction in seven patients (43.8%). The most common transition was bosentan to macitentan in eight patients (50%). Fifteen patients (93.8%) tolerated the transition after a median follow-up of 6.5 months with minor adverse events occurring in four patients (25%). In 11 patients, 6-min walk distance (6MWD) was unchanged comparing baseline to post transition measurements with a median change of +8 m (range: −50 to + 70; P = 0.39). Nine patients (81.8%) had stable (within 15% margin) or significant improvement (increase by ≥15%) in 6MWD after transition. All patients demonstrated stable or improved WHO FC after transition. There were no significant changes after transition in hemodynamics, N-terminal pro-brain natriuretic peptide (NT-proBNP) values, or Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk scores. In our study, transitioning patients from bosentan and sildenafil to alternative therapy was safe and resulted in clinical stability.

Pharmacological Interactions in the Elderly

Pharmacological therapy in the elderly is particularly complicated and challenging. Due to coexistence of three main predisposing factors (advanced age, multiple morbidity and polypharmacotherapy), this group of patients is prone to occurrence of drug interactions and adverse effects of incorrect drug combinations. Since many years patient safety during the treatment process has been one of key elements for proper functioning of healthcare systems around the world, thus different preventive measures have been undertaken in order to counteract factors adversely affecting the therapeutic effect. One of the avoidable medical errors is pharmacological interactions. According to estimates, one in six elderly patients may be at risk of a significant drug interaction. Hence the knowledge about mechanisms and causes of drug interactions in the elderly, as well as consequences of their occurrence are crucial for planning the process of pharmacotherapy. For the purpose of pharmacovigilance, a review of available methods and tools gives an insight into possible ways of preventing drug interactions. Additionally, recognizing the actual scale of this phenomenon in geriatric population around the world emphasizes the importance of a joint effort among medical community to improve quality of pharmacotherapy.

Cannabidiol: From Drug Interaction Potential to Modulation of the Gut Microbiome

Objectives Cannabidiol (CBD) is the major non-psychotropic phytocannabinoid present in Cannabis sativa. In 2018, Congress designated select C. sativa cultivars as “hemp” removing them from the DEA's list of controlled substances. As a result, CBD-containing hemp extracts and other CBD products are now widely available and heavily marketed, yet their FDA regulatory status is still hotly debated. Further complicating the debate is CBD's vastly under-researched safety profile. Safety concerns yet to be adequately addressed include CBD's drug interaction potential and its effect on the gut microbiome. Methods Using acetaminophen (APAP), the most commonly ingested over-the-counter pain medication, we demonstrated that CBD-rich cannabis extract (CRCE) poses a significant drug interaction risk. Results Mice exposed to both CRCE and APAP developed severe liver injury. This hepatotoxicity, however, was not observed when either CRCE or APAP were administered separately. Importantly, this injury was observed in two different strains of mice with susceptibilities seemingly linked to sex (female) and age (older animals). Furthermore, both beneficial and adverse effects of CRCE on the gut microbiome were observed. Specifically, CRCE exposure increased the relative abundance of the beneficial gut microbe, Akkermansia muciniphila, however, an overall decrease in the relative abundance of all gut bacterial species was noted. This decrease was paralleled by numerous pro-inflammatory responses in the proximal jejunum and colon. Conclusions Taken together, these findings raise significant concerns about the safety of widespread CBD usage and underlines the need for additional well-designed studies into its safety and efficacy. Funding Sources NIGMS 1P20 GM109005.

Peripheral neuropathy in non-Hodgkin’s lymphoma patients receiving vincristine with and without aprepitant/fosaprepitant

Background Peripheral neuropathy is a common treatment-related adverse effect associated with vincristine. Vincristine is a major CYP3A4 substrate and is often administered alongside the neurokinin-1 (NK-1) receptor antagonists, aprepitant or fosaprepitant, which are moderate CYP3A4 inhibitors. This inhibition may result in increased concentrations of vincristine and an increased incidence of toxicity. Objective The primary objective of this study was to investigate if there is a clinically significant drug interaction between vincristine and aprepitant or fosaprepitant resulting in early-onset peripheral neuropathy. The secondary objective of this study was to investigate the cumulative rate of chemotherapy-induced peripheral neuropathy (CIPN). Methodology This was a single-centered, retrospective, cohort chart review. Patients receiving vincristine-based chemotherapy between 1 July 2010 through 30 June 2018 were identified and reviewed for concomitant use of aprepitant or fosaprepitant and incidence of neuropathy. Early-onset CIPN was defined as neuropathy onset during the first cycle of chemotherapy. Results A total of 115 subjects were retrospectively reviewed over the study period, of whom 71 were included in the aprepitant/fosaprepitant group and 44 were included in the group without a NK-1 receptor antagonist. Of the subjects who received aprepitant/fosaprepitant, 26.7% experienced early-onset peripheral neuropathy as compared to 22.7% in the group without a NK-1 receptor antagonist ( P = 0.627). Overall, CIPN was higher in the group who received aprepitant/fosaprepitant compared to the group without (56% vs. 36%, P = 0.036). Conclusion There appears to be an increased risk of CIPN with the concomitant use of vincristine and aprepitant or fosaprepitant.

ASSESSMENT OF DRUG INTERACTIONS IN OUTPATIENT PRESCRIPTIONS IN HUE UNIVERSITY OF MEDICINE AND PHARMACY HOSPITAL

Background: The combination of drugs in treatment is inevitable, especially in multiple diseases and multiple symptoms. This is the leading cause of occurrence of drug - drug interactions. Objectives: (1) To identify clinically significant drug interactions in outpatient prescriptions in Hue University of Medicine and Pharmacy Hospital, (2) To build a management guideline of clinically significant drug interactions in Hue University of Medicine and Pharmacy Hospital. Materials and methods: 5338 outpatient prescriptions were collected from Pharmacy Faculty – Hue University of Medicine and Pharmacy Hospital from 1st to 31st October 2017, using cross-sectional descriptive study method. Results and Conclusion: The list of 20 clinically significant drug interaction pairs was identified and a management guideline for each interacting pair was built. The prevalence of prescriptions with drug interactions was 6.7%. The most commonly identified drug interaction pair was clopidogrel and proton pump inhibitor (1.59%). The occurrence of drug interactions increased with increase in the age of patients and the number of drugs prescribed (p < 0.05). Key words: combination of drugs, drug interaction, clinically significant, prescription, outpatient

Drug Interactions With Oral Inhaled Medications

Objective: To evaluate the potential for drug interactions with oral inhaled medications (OIMs). OIMs include bronchodilators (β-agonists and antimuscarinics), corticosteroids, combination products (2 or more agents combined within a single inhalation device), antibiotics, prostacyclins, anesthetics, acetylcysteine, mucolytics, insulin, antivirals, nitric oxide, and nicotine replacement. Data Sources: A systemic literature search (1980 to May 2018) was performed using PubMed and EBSCO to locate relevant articles. The MESH terms used included each specific medication available as an OIM as well as “drug interactions.” DAILYMED was used for product-specific drug interactions. Study Selection and Data Extraction: The search was conducted to identify drug interactions with OIMs. The search was limited to those articles studying human applications with OIMs and publications using the English language. Case reports, clinical trials, review articles, treatment guidelines, and package labeling were selected for inclusion. Data Synthesis: Primary literature and package labeling indicate that OIMs are subject to pharmacokinetic and pharmacodynamics interactions. The most frequently identified clinically significant drug interaction is an inhaled corticosteroid when combined with a potent CYP 450 inhibitor such as a protease inhibitor or antifungal. Conclusions: The available literature indicates that OIMs are associated with clinically significant drug interactions and subsequent adverse reactions. Clinicians in all practice settings should be mindful of this potential to minimize adverse effects and optimize therapy.