Food-drug Interactions Research Articles

Poster: MPN-028: Heart Failure: A Cause of Polypharmacy, Drug-Drug, and Food-Drug Interactions in Essential Thrombocythemia

Poster: MPN-028: Heart Failure: A Cause of Polypharmacy, Drug-Drug, and Food-Drug Interactions in Essential Thrombocythemia

Importance of attributes and willingness to pay for oral anticoagulant therapy in patients with atrial fibrillation in China: A discrete choice experiment.

Adherence to oral anticoagulant therapy in patients with atrial fibrillation (AF) in China is low. Patient preference, one of the main reasons for discontinuation of oral anticoagulant therapy, is an unfamiliar concept in China. A discrete choice experiment (DCE) was conducted to quantify patient preference on 7 attributes of oral anticoagulant therapy: antidote (yes/no), food-drug interaction (yes/no), frequency of blood monitoring (no need, every 6/3/1 month[s]), risk of nonfatal major bleeding (0.7/3.1/5.5/7.8[%]), risk of nonfatal stroke (ischemic/hemorrhagic) or systemic embolism (0.6/3.2/5.8/8.4[%]), risk of nonfatal acute myocardial infarction (AMI) (0.2/1.0/1.8/2.5[%]), and monthly out-of-pocket cost (0/120/240/360 RMB) (0 to 56 USD). A total of 16 scenarios were generated by using D-Efficient design and were randomly divided into 2 blocks. Eligible patients were recruited and interviewed from outpatient and inpatient settings of 2 public hospitals in Beijing and Shenzhen, respectively. Patients were presented with 8 scenarios and asked to select 1 of 3 options: 2 unlabeled hypothetical treatments and 1 opt-out option. Mixed logit regression model was used for estimating patients' preferences of attributes of oral anticoagulants and willingness to pay (WTP) with adjustments for age, sex, education level, income level, city, self-evaluated health score, histories of cardiovascular disease/other vascular disease/any stroke/any bleeding, and use of anticoagulant/antiplatelet therapy. A total of 506 patients were recruited between May 2018 and December 2019 (mean age 70.3 years, 42.1% women). Patients were mainly concerned about the risks of AMI (β: -1.03; 95% CI: -1.31, -0.75; p < 0.001), stroke or systemic embolism (β: -0.81; 95% CI: -0.90, -0.73; p < 0.001), and major bleeding (β: -0.69; 95% CI: -0.78, -0.60; p < 0.001) and were willing to pay more, from up to 798 RMB to 536 RMB (124 to 83 USD) monthly. The least concerning attribute was frequency of blood monitoring (β: -0.31; 95% CI: -0.39, -0.24; p < 0.001). Patients had more concerns about food-drug interactions even exceeding preferences on the 3 risks, if they had a history of stroke or bleeding (β: -2.47; 95% CI: -3.92, -1.02; p < 0.001), recruited from Beijing (β: -1.82; 95% CI: -2.56, -1.07; p < 0.001), or men (β: -0.96; 95% CI: -1.36, -0.56; p < 0.001). Patients with lower educational attainment or lower income weighted all attributes lower, and their WTP for incremental efficacy and safety was minimal. Since the patients were recruited from 2 major hospitals from developed cities in China, further studies with better representative samples would be needed. Patients with AF in China were mainly concerned about the safety and effectiveness of oral anticoagulant therapy. The preference weighting on food-drug interaction varied widely. Patients with lower educational attainment or income levels and less experience of bleeding or stroke had more reservations about paying for oral anticoagulant therapies with superior efficacy, safety, and convenience of use.

Nanoparticulate Drug Delivery Strategies to Address Intestinal Cytochrome P450 CYP3A4 Metabolism towards Personalized Medicine.

Drug dosing in clinical practice, which determines optimal efficacy, toxicity or ineffectiveness, is critical to patients’ outcomes. However, many orally administered therapeutic drugs are susceptible to biotransformation by a group of important oxidative enzymes, known as cytochrome P450s (CYPs). In particular, CYP3A4 is a low specificity isoenzyme of the CYPs family, which contributes to the metabolism of approximately 50% of all marketed drugs. Induction or inhibition of CYP3A4 activity results in the varied oral bioavailability and unwanted drug-drug, drug-food, and drug-herb interactions. This review explores the need for addressing intestinal CYP3A4 metabolism and investigates the opportunities to incorporate lipid-based oral drug delivery to enable precise dosing. A variety of lipid- and lipid-polymer hybrid-nanoparticles are highlighted to improve drug bioavailability. These drug carriers are designed to target different intestinal regions, including (1) local saturation or inhibition of CYP3A4 activity at duodenum and proximal jejunum; (2) CYP3A4 bypass via lymphatic absorption; (3) pH-responsive drug release or vitamin-B12 targeted cellular uptake in the distal intestine. Exploitation of lipidic nanosystems not only revives drugs removed from clinical practice due to serious drug-drug interactions, but also provide alternative approaches to reduce pharmacokinetic variability.

Effects of camel milk hydrolysate on blood pressure and biochemical parameters in fructose-induced hypertensive rats

PurposeThis study aims to investigate the antihypertensive effect of camel milk hydrolysate in rats with fructose-induced hypertension.Design/methodology/approachThe antihypertensive effect of fermented camel milk was determined using 6 groups comprising 36 Wistar male rats. Blood pressure of rats was altered via exposure to a 10% fructose (w/v) diet in drinking water for 3 weeks before conducting 21 days of treatment. The authors conducted the experiment for short and long term using different doses of 800 and 1,200 mg/kg body weight. Serum was used to assay total cholesterol (TC), triglyceride (TG), glucose and insulin levels using standard biochemical kits.FindingsThe group that received 1,200 mg hydrolysate camel milk (HM) has significantly (p = 0.003) reduced systolic and diastolic blood pressure after a short exposure time (4–8 h). These effects were significantly (p = 0.005) comparable to the nifedipine (NIF) drug group. Similar long-term (21 days) effects on blood pressure were observed in 1,200 mg HM and NIF groups. Angiotensin-converting enzyme (ACE) activity and levels were also reduced in a correlation with blood pressure reduction only in HM1200 and HM800 treated groups. The authors observed no significant effect on blood pressure in groups receiving the 800 mg HM or 1,200 mg unhydrolyzed camel milk (UM). Rats receiving the 10% fructose diet showed significant differences from control rats regarding their blood biochemistry, including TG, TC, blood glucose and insulin levels. Rats in groups NIF, HM1200 and HM800 showed a significant (p < 0.05) reduction in serum glucose, insulin, TG and TC levels toward the baseline level.Research limitations/implicationsFurther mechanistic investigation on the HM antihypertensive activity is highly recommended before suggesting HM as a product to reduce blood pressure. While drug–food interaction between HM and antihypertensive drugs, especially ACE inhibitors, is probable, UM seems not to affect blood pressure or ACE activity and therefore is expected to have no or minimal effects on the activity of other antihypertensive drugs. Investigation of ACE expression from various organs including lungs and leukocytes is highly recommended in future works using sodium dodecyl-sulfate polyacrylamide gel electrophoresis and western blot analysis or reverse transcription polymerase chain reaction.Originality/valueNo previous studies have measured the antihypertensive activity of milk hydrolysate mediated by the reduction of ACE activity and levels in plasma. Mechanisms involved in attenuating the levels of ACE warrant further investigation.

The Clinical Significance of Drug-Food Interactions of Direct Oral Anticoagulants.

Cardiovascular diseases are the most common cause of death in the world. For almost 60 years, vitamin K antagonists (VKAs) were the mainstay of anticoagulation therapy, but in recent years direct oral anticoagulants (DOACs) have become the anticoagulant treatment of choice. DOACs were initially considered drugs with no significant food interactions; however, clinical observations from daily practice have proved otherwise as interactions with food ingredients have been reported. Food, dietary supplements or herbs may contain substances that, when administered concomitantly with DOACs, can potentially affect the plasma concentration of the drugs. The aim of this paper was to evaluate the clinical significance of drug–food interactions of DOACs, such as dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban. Patients treated with anticoagulants should avoid products containing St. John’s wort and take special care with other food ingredients. As the interest in dietary supplements is on the rise, healthcare providers can contribute to the development of well-designed clinical trials on interactions between DOACs and food, and distribute sufficient knowledge about the proper use of these supplements among patients.

Knowledge, attitudes and practices of healthcare professionals regarding drug-food interactions: a scoping review.

Drug-food interactions (DFIs) are a problem in clinical practice as they can alter the bioavailability of drugs and nutrients and may lead to various adverse effects. Healthcare professionals (HCPs) play a significant role in counselling patients and preventing these interactions. Knowledge, attitudes and practices (KAPs) regarding DFIs are, therefore, vital to ensure that they carry out their role efficiently. This review maps evidence on KAPs of HCPs regarding DFIs and highlights gaps for further research. A systematic literature search for the period from 1990 to 2018 was done using Google Scholar, PubMed and ScienceDirect. Keywords such as 'knowledge, attitudes, practices, healthcare professionals, drug-food interactions' in combination with the Boolean operator (AND) were used. Articles published only in English that described KAPs of HCPs relating to DFIs were included. Twelve studies were included in this review. Inadequate knowledge was observed among the HCPs as they were unable to identify important DFIs. The HCPs had a positive attitude towards acquiring knowledge, reporting and counselling patients on DFIs. Most of the medical residents felt that they were inadequately trained on DFIs and over half believed that DFIs were only slightly important in clinical practice. Deficits exist in the KAPs of HCPs regarding DFIs. An educational intervention targeting HCPs is recommended. Further research assessing the KAPs of the HCPs is required as the small number of studies conducted was a limitation.

Medication Errors During Treatment with New Oral Anticancer Agents: Consequences for Clinical Practice Based on the AMBORA Study.

Patients treated with oral anticancer agents (e.g., kinase inhibitors) are a high-risk population for medication errors due to, for example, polymedication, age, and limited adherence. Systematic evaluations regarding frequencies and causes of medication errors and resulting harm are lacking. Our previously published multicenter randomized AMBORA trial revealed that an intensified support by clinical pharmacologists/pharmacists for patients and the treatment team considerably reduced drug-related problems and improved patient-reported outcomes. Using this database, we performed a comprehensive, additional analysis focusing on medication errors related to the patients' complete medication with consideration of the antitumor agents, concomitantly administered drugs, and herb/food intake. Two hundred two patients starting a new oral anticancer drug regardless of the tumor entity were included. Clinical pharmacologists/pharmacists performed advanced medication reviews for 12weeks. Medication errors were characterized regarding type, cause, patient harm, and the involved medicines. We detected 1.7 medication errors per patient (335/202). Of the medication errors (216/335), 64.5% occurred within the concomitant medication. Patients caused 28.4% of the medication errors. There were 67.8% detected immediately after the start of the new oral regimen, and 14.9% resulted in temporary harm. Drug-drug or drug-food interactions accounted for 24.8% of the medication errors. Patients and physicians need to be addressed in strategies for systematic reduction of medication errors during treatment with new oral antitumor drugs. Clinical decision support systems focusing on drug-drug interactions capture only a minority of the medication errors. Specialists with expertise in clinical pharmacology/pharmacy should support both the treating physicians as well as the patients for improved patient safety.

Successful nutrition-based approach in Gilles de la Tourette syndrome heralding drug side effects: A case report and short review

Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by tics that frequently hide complex spectra with behavioral disorders. Medical intervention should rely on multimodal strategies including nutritional assessment and dietetic support as patients can suffer from impulsive eating and the medications often cause metabolic side effects. We present for the first time the case and treatment of a boy suffering from a severe phenotype of TS who experienced hyperphagia, weight gain, gastrointestinal disturbances, and nutritional delusions. Brief annotations about both differential nutritional assessment and underlying drug-related implications are also offered. The parents were educated on healthy eating, drug-food interactions, and hunger delay techniques. After the symptom-driven personalization of drug therapy, the start of cognitive behavioral therapy, and the escalation of the dietetic plan, the boy managed to lose weight and maintain healthy eating habits at the three-year follow-up. We reaffirm the importance of not only including a nutritionist in the management team of patients with TS, but also of assuring that the nutritional protocol perfectly integrates a comprehensive strategy in order to obtain long-term results.

Use of the failure mode and effect analysis tool in the clinical medication process in an intensive care unit

Objective: To describe failure modes and establish contingency measures related to the clinical medication process using medical prescriptions of patients admitted to an Intensive Respiratory Therapy Unit (UTIR), using the Failure Mode and Effects Analysis (FMEA) tool. Methods: This is a descriptive and cross-sectional study carried out in an Intensive Care Unit of a public hospital in Fortaleza, Brazil, from November/2015 to March/2016. Study population included adults aging ≥ 18 years in intensive care at the UTIR. The study included the medical prescriptions released on Mondays, Wednesdays, and Fridays. The study was divided in five phases: situational diagnosis, formation of a multiprofessional team, assessment of failure modes (FM), monitoring of FM and calculation of the priority coefficient (PC). In the FM assessment, scoring of the three indicators of the FMEA was used within a range of 1-10, whereas a score of 10 characterized the most concerning situation. Therefore, the indicators gravity (G), prevalence (P) and detection (D) were analyzed. The study was carried out with an active interaction between the subjects of the group and several in-person and virtual sessions were performed. Drugs used in the study were categorized for therapeutic class, according to the Anatomical Therapeutic Chemical Classification System. Data analysis was performed using Microsoft Office Excel® 2013 software. Results: 301 prescriptions were analyzed, with the identification of 452 FMs, which related mostly to systemic antibacterials (21.6%, n = 8), psycholeptics (13.5%, n = 5) and antithrombotic agents (10.8%, n = 4). FMs were divided in eleven categories, from which “drug interaction” (36.8%; n = 14), “dose adjustment” (21.1%, n = 8) and “food-drug interaction” (7.9%, n = 3) were the most frequent. The PC of the detected FMs varied between 28 and 294, and 42.1% (n = 16) of them presented PC above 100. Median of the indicators G (6 – min: 3; max: 9), D (7 – min: 3; max 7) and priority coefficient (72 – min: 28; max: 294) indicate that FM had generally moderate gravity, low prevalence and low detection. For the majority of FMs (72.7%, n = 28), the chosen conduct was ‘not to accept’ and the established contingency measure included a sentinel event notification. Conclusion: The use of FMEA enabled the identification, classification, and prioritization of risks of the clinical medication process in the UTIR. This study indicates the need to implement measures that increase safety in the clinical practice of the study Intensive Care Unit.

Use of Physiologically Based Pharmacokinetic Modeling for Predicting Drug-Food Interactions: Recommendations for Improving Predictive Performance of Low Confidence Food Effect Models.

Food can alter drug absorption and impact safety and efficacy. Besides conducting clinical studies, in vitro approaches such as biorelevant solubility and dissolution testing and in vivo dog studies are typical approaches to estimate a drug's food effect. The use of physiologically based pharmacokinetic models has gained importance and is nowadays a standard tool for food effect predictions at preclinical and clinical stages in the pharmaceutical industry. This manuscript is part of a broader publication from the IQ Consortium's food effect physiologically based pharmacokinetic model (PBPK) modeling working group and complements previous publications by focusing on cases where the food effect was predicted with low confidence. Pazopanib-HCl, trospium-Cl, and ziprasidone-HCl served as model compounds to provide insights into why several food effect predictions failed in the first instance. Furthermore, the manuscript depicts approaches whereby PBPK-based food effect predictions may be improved. These improvements should focus on the PBPK model functionality, especially better reflecting fasted- and fed-state gastric solubility, gastric re-acidification, and complex mechanisms related to gastric emptying of drugs. For improvement of in vitro methodologies, the focus should be on the development of more predictive solubility, supersaturation, and precipitation assays. With regards to the general PBPK modeling methodology, modelers should account for the full solubility profile when modeling ionizable compounds, including common ion effects, and apply a straightforward strategy to account for drug precipitation.

Polypharmacy and Malnutrition Management of Elderly Perioperative Patients with Cancer: A Systematic Review.

Malnutrition, which commonly occurs in perioperative patients with cancer, leads to decreased muscle mass, hypoalbuminemia, and edema, thereby increasing the patient’s risk of various complications. Thus, the nutritional management of perioperative patients with cancer should be focused on to ensure that surgical treatment is safe and effective, postoperative complications are prevented, and mortality is reduced. Pathophysiological and drug-induced factors in elderly patients with cancer are associated with the risk of developing malnutrition. Pathophysiological factors include the effects of tumors, cachexia, and anorexia of aging. Metabolic changes, such as inflammation, excess catabolism, and anabolic resistance in patients with tumor-induced cancer alter the body’s ability to use essential nutrients. Drug-induced factors include the side effects of anticancer drugs and polypharmacy. Drug–drug, drug–disease, drug–nutrient, and drug–food interactions can significantly affect the patient’s nutritional status. Furthermore, malnutrition may affect pharmacokinetics and pharmacodynamics, potentiate drug effects, and cause side effects. This review outlines polypharmacy and malnutrition, the impact of malnutrition on drug efficacy, drug–nutrient and drug–food interactions, and intervention effects on polypharmacy or cancer cachexia in elderly perioperative patients with cancer.

Severe angioedema induced by tomato soup with alprazolam and muscle relaxant drug: A rare and complex drug-food interaction

Molecular interactions at the level of drug and food may lead to the reduced or enhanced effect of a concomitantly given drug or food nutrient. The resultant effects of such interactions may sometimes be severe to life-threatening. Here, we present a rare case of a 40-year-old male patient who developed severe angioedema secondary to drug-food interaction. The patient presented in emergency with complaints of angioedema face, rashes, and difficulty in breathing. History revealed that the patient had been prescribed analgesic muscle relaxant Flexon MR (t.i.d) for severe backache 1 day before. On day 2, the patient self-medicated with tablet alprazolam for inducing sleep followed by intake of hot concentrated tomato soup (350 ml). Within ½ h, the patient took Flexon MR. Following Flexon MR, the patient went drowsy and developed angioedema face and rashes on the whole body with difficulty in breathing. The patient was given injection adrenaline (i.m) injection followed by an injection of chlorpheniramine (i/m) stat. After stabilization of vitals, the patient was discharged.

Concepts and preconceptions on the use of direct oral anticoagulants in Italy: a Delphi consensus panel of the Atherosclerosis Thrombosis, Vascular Biology Study Group (ATBV)

In the last decade, direct oral anticoagulants (DOACs) have entered the clinical practice of different specialists for the prevention of cardioembolic stroke in patients with non-valvular atrial fibrillation (NVAF) and the prevention and treatment of venous thromboembolism (VTE). Owing to the persistent uncertainties about the use of DOACs in daily clinical scenarios not fully explored in the clinical trials, we conducted a national Delphi consensus regarding issues deemed interesting by the Italian Atherosclerosis, Thrombosis and Vascular Biology (ATBV) Study Group in relation to: (i) elderly and/or frail patients; (ii) chronic kidney disease; (iii) drug-drug interactions; (iv) lower doses and safety; (v) criteria for choosing individual drugs and compliance; (vi) VTE in the cancer patient. Eighty-four Italian clinicians (cardiologists, internists, geriatricians, neurologists and hematologists) expressed their level of agreement on each statement using a 5-point Likert scale (1: very much in disagreement, 2: disagreement, 3: partial agreement, 4: agreement, 5: very much in agreement). In particular, 1-2 selections were considered as disagreement, while 3-5 selections were considered as agreement. A ≥66% agreement between the participants for each statement was considered consensus. In general, a broad and general awareness and sharing of the methods of use of DOACs emerged from our initiative, and in particular their preferential indication in the elderly population and in frail patients or with renal insufficiency or oncological, always following the prescription indications and dose reduction criteria. The importance of being aware of drug-drug interactions has also been underlined in a concordant way, as well as simplicity of treatment in the multi-treated patient. In view of the persistent, albeit limited (12%), absence of consensus on some issues, with regard to the frail patient, drug-food interactions and availability of antidote, the acquisition of further evidence and a persistent educational effort are nonetheless indicated.

Patient-Reported Outcomes Through 1 Year of an HIV-1 Clinical Trial Evaluating Long-Acting Cabotegravir and Rilpivirine Administered Every 4 or 8Weeks (ATLAS-2M).

BackgroundAdvances in HIV-1 therapeutics have led to the development of a range of daily oral treatment regimens, which share similar high efficacy rates. Consequently, more emphasis is being placed upon the individual’s experience of treatment and impact on quality of life. The first long-acting injectable antiretroviral therapy for HIV-1 (long-acting cabotegravir + rilpivirine [CAB + RPV LA]) may address challenges associated with oral treatment for HIV-1, such as stigma, pill burden/fatigue, drug–food interactions, and adherence. Patient-reported outcomes (PROs) collected in an HIV-1 clinical trial (ATLAS-2M; NCT03299049) comparing participants’ experience with two dosing regimens (every 4 weeks [Q4W] vs. every 8 weeks [Q8W]) of CAB + RPV LA are presented herein.MethodsPRO endpoints evaluated through 48 weeks of therapy included treatment satisfaction (HIV Treatment Satisfaction Questionnaire [HIVTSQ]), treatment acceptance (“General Acceptance” domain of the Chronic Treatment Acceptance [ACCEPT®] questionnaire), acceptability of injections (Perception of Injection [PIN] questionnaire), treatment preference (questionnaire), and reasons for switching to/continuing long-acting therapy (exploratory endpoint; questionnaire). Participants were randomized 1:1 to receive CAB + RPV LA Q8W or Q4W. Results were stratified by prior CAB + RPV exposure in either preplanned or post hoc analyses.ResultsOverall, 1045 participants were randomized to the Q8W (n = 522) and Q4W (n = 523) regimens; 37% (n = 391/1045) had previously received CAB + RPV in ATLAS. For participants without prior CAB + RPV exposure, large increases from baseline were reported in treatment satisfaction in both long-acting arms (HIVTSQ status version), with Q8W dosing statistically significantly favored at Weeks 24 (p = 0.036) and 48 (p = 0.004). Additionally, improvements from baseline were also observed in the “General Acceptance” domain of the ACCEPT questionnaire in both long-acting arms for participants without prior CAB + RPV exposure; however, no statistically significant difference was observed between arms at either timepoint (Week 24, p = 0.379; Week 48, p = 0.525). Significant improvements (p < 0.001) in the “Acceptance of Injection Site Reactions” domain of the PIN questionnaire were observed from Week 8 to Weeks 24 and 48 in both arms for participants without prior CAB + RPV exposure. Participants with prior CAB + RPV exposure reported high treatment satisfaction (mean [HIVTSQ status version]: Q8W 62.2/66.0; Q4W 62.0/66.0), treatment acceptance (mean: Q8W 89.3/100; Q4W 91.2/100), and acceptance of injection site reactions (mean [5 = not at all acceptable; 1 = totally acceptable]: Q8W 1.72; Q4W 1.59) at baseline/Week 8 that were maintained over time. Participants without prior CAB + RPV exposure who received Q8W dosing preferred this regimen over oral CAB + RPV (98%, n = 300/306). Among those with prior Q4W exposure, 94% (n = 179/191) preferred Q8W dosing versus Q4W dosing (3%, n = 6/191) or oral CAB + RPV (2%, n = 4/191).ConclusionsBoth long-acting regimens provided high treatment satisfaction and acceptance, irrespective of prior CAB + RPV exposure, with most participants preferring Q8W dosing over both the Q4W regimen and their previous daily oral regimen. The PRO data collected at Week 48 support the therapeutic potential of CAB + RPV LA.FundingViiV Healthcare and Janssen.Trial RegistrationATLAS-2M: ClinicalTrials.gov NCT03299049, registered October 2, 2017.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40271-021-00524-0.

Prescribing Pattern and Pharmacist Intervention in Anticoagulation at A Tertiary Care Teaching Hospital, Coimbatore, India

Objective: To assess the prescribing pattern and pharmacist intervention in anti-coagulation at a tertiary care teaching hospital, Coimbatore, India Methodology: Data was gathered utilizing a well-structured data collection structure which includes patient's demographics, clinical data which includes (indication for anticoagulation therapy, wanted INR range, anticipated length of therapy, anticoagulation therapy got), social propensities, past medical history, current prescriptions and the prescribed oral anticoagulant (Warfarin/Acitrom). INR values were observed for the patients remembered for the investigation and dosage adjustment was finished by standard convention dependent on the INR value. The patients were also provided with effective counseling regarding the therapy and dietary modifications. All the patients were monitored for any adverse drug events/effects or any possible drug and food interactions during the study period. In case of any reported adverse events/drug associations in the anticoagulation facility, the legitimate intervention was finished by the clinical pharmacist in relationship with a physician to accomplish objective drug therapy. Result: During our study period, 86 patients were forwarded by the physicians to the clinical pharmacist managing the oral anticoagulation clinic. Only 70 patients could complete the study, where 4 patients did not visit the clinic, other 12 patients did not meet the inclusion criteria and hence they are excluded. The data were collected using data collection form for the study sample. After the interventional study, there was a significant improvement in patients maintaining % of INRs which were in target therapeutic range, % of TTR along with decreased adverse effects. It was also found that the patient’s awareness of the target INR values is correlated with the improved accuracy of anticoagulation control. Hence, our study results reflect the need for a clinical pharmacist in oral anticoagulation management and the necessity of implementing anticoagulation services in various hospital settings. Conclusion: the clinical pharmacist managing anticoagulation service was able to achieve the INRs of the patient in to target therapeutic range by proper and timely dose adjustments based on the INR value, to identify adverse drug reactions/ adverse events, drug-drug interactions, and drug-food interactions and bring about proper interventions by working in association with physicians. Keywords: anticoagulant, Clinical pharmacist intervention, INR results, Physician intervention,

Visualizing Food-Drug Interactions in the Thériaque Database.

This paper presents a prototype for the visualization of food-drug interactions implemented in the MIAM project, whose objective is to develop methods for the extraction and representation of these interactions and to make them available in the Thériaque database. The prototype provides users with a graphical visualization showing the hierarchies of drugs and foods in front of each other and the links between them representing the existing interactions as well as additional details about them, including the number of articles reporting the interaction. The prototype is interactive in the following ways: hierarchies can be easily folded and unfolded, a filter can be applied to view only certain types of interactions, and details about a given interaction are displayed when the mouse is moved over the corresponding link. Future work includes proposing a version more suitable for non-health professional users and the representation of the food hierarchy based on a reference classification.

Cogent role of flavonoids as key orchestrators of chemoprevention of hepatocellular carcinoma: A review.

Chemopreventive approaches with food-derived phytochemicals are progressively rising as a significant aspect of tumor management and control. Herein, we have showcased the major phytoconstituents belonging to the group of flavanoid, as anti-cancer agents used for the treatment and prevention of hepatocellular carcinoma (HCC). Sorafenib is the sole drug used for the treatment of advanced HCC, but its clinical application is limited because of its severe adverse effects and drug resistance. Diet-based chemoprevention seems to be the way forward for this disease of malignant nature. As HCC is derived from a chronic inflammatory milieu, the regular incorporation of bioactive phytochemicals in the diet will confer protection and prevent progression to hepatocarcinogenesis. Many preclinical studies proved that the health benefits of flavonoids confer cytotoxic potential against various types of cancers including hepatocellular carcinoma. As flavonoids with excellent safety profile are abundantly present in common vegetables and fruits, they can be better utilized for chemoprevention and chemosensitization in such chronic condition. This review highlights the plausible role of the eight most promising flavonoids (Curcumin, Kaempferol, Resveratrol, Quercetin, Silibinin, Baicalein, Galangin and Luteolin) as key orchestrators of chemoprevention in hepatocellular carcinoma with preclinical and clinical evidence. An attempt to address the challenges in its clinical translation is also included. This review also provides an insight into the close association of HCC and metabolic disorders which may further decipher the chemopreventive effect of dietary bioactive from a proof of concept to extensive clinical translation. PRACTICAL APPLICATIONS: According to GLOBOCAN 2020 database, it is estimated that 905,677 new cases of liver cancer and approximately 830,180 deaths related to that. The cancer incidence and mortality are almost similar as it is diagnosed at an advanced stage in patients where systemic drug therapy is the sole approach. Due to the emergence of multidrug resistance and drug-related toxicities, most of the patient can not adhere to the therapy regimen. Flavonoids are known to be a potential anticancer agent with an excellent safety profile. These are found to be effective preclinically against hepatocellular carcinoma through modulation of numerous pathways in hepatocarcinogenesis. But, the bioavailability issue, lack of well designed-validated clinical evidence, the possibility of food-drug interaction etc limit its clinical utility. The research inputs mainly to overcome pharmacokinetic issues along with suitable validation of efficacy and toxicity will be a critical point for establishing flavonoids as an effective, safe, affordable therapeutics.

Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids.

Acacetin, apigenin, chrysin, and pinocembrin are flavonoid aglycones found in foods such as parsley, honey, celery, and chamomile tea. Flavonoids can act as substrates and inhibitors of the CYP3A4 enzyme, a heme containing enzyme responsible for the metabolism of one third of drugs on the market. The aim of this study was to investigate the inhibitory effect of selected flavonoids on the CYP3A4 enzyme, the kinetics of inhibition, the possible covalent binding of the inhibitor to the enzyme, and whether flavonoids can act as pseudo-irreversible inhibitors. For the determination of inhibition kinetics, nifedipine oxidation was used as a marker reaction. A hemochromopyridine test was used to assess the possible covalent binding to the heme, and incubation with dialysis was used in order to assess the reversibility of the inhibition. All the tested flavonoids inhibited the CYP3A4 enzyme activity. Chrysin was the most potent inhibitor: IC50 = 2.5 ± 0.6 µM, Ki = 2.4 ± 1.0 µM, kinact = 0.07 ± 0.01 min−1, kinact/Ki = 0.03 min−1 µM−1. Chrysin caused the highest reduction of heme (94.5 ± 0.5% residual concentration). None of the tested flavonoids showed pseudo-irreversible inhibition. Although the inactivation of the CYP3A4 enzyme is caused by interaction with heme, inhibitor-heme adducts could not be trapped. These results indicate that flavonoids have the potential to inhibit the CYP3A4 enzyme and interact with other drugs and medications. However, possible food–drug interactions have to be assessed clinically.

Evaluation system for cell-permeable CYP3A4 inhibitory activity using 1α,25-dihydroxy-vitamin D3-induced intestinal cell lines

We developed an assay system to evaluate the cytochrome P450 (CYP) 3A4-inhibitory activity of compounds, taking account of their cellular permeability, using intestine-derived cell lines pre-treated with the CYP3A4 inducer 1α,25-dihydroxy-vitamin D3 (250 nM). Ketoconazole (KTZ), saquinavir (SQV), naringin, naringenin (NGE), bergamottin (BG), 6',7'-dihydroxybergamottin (DHBG), epigallocatechin gallate (EGCG), and resveratrol (RES) were evaluated as known CYP3A4 inhibitors. The apparent IC50 (IC50,app) values of known inhibitors were determined in Caco-2 cells with 10 µM midazolam as a CYP3A4 substrate, and compared with the IC50 values in a human liver microsome assay. SQV and BG with high lipophilicity and good membrane permeability show similar concentrations inside and outside the cells, and consequently IC50,app and IC50 are similar. KTZ, EGCG, DHBG, NGE, and RES showed a difference between IC50 and IC50,app. This is considered to result from a difference between the intracellular and extracellular concentrations of the compound, which is likely due to the involvement of efflux and/or influx transporters. This method to evaluate CYP inhibition taking account of membrane permeation should be helpful to assess the potential clinical relevance of drug-drug or drug-food interactions in the gastrointestinal tract.

The Effect of Pomegranate Juice on the Expression of Some Murine UDP-Glucuronosyltransferases Genes.

Food-drug interactions may lead to suppression or induction of drug metabolizing enzymes. Pomegranate is a commonly used fruit in folk medicine all over the world. Data concerning the effect of pomegranate on the activity of UDP-glucuronosyltransferases (UGTs) is scarce. The purpose of this work was to investigate the effect of pomegranate juice ingestion on the transcription of ugt2b1, ugt2a3, and ugt1a9 in the liver and small intestine of male mice. Pomegranate juice was administered to 10 male mice for 14 days in drinking bottles instead of water. Ten control mice received water in the drinking bottles. On the 15th day, the mice were sacrificed and the liver and the small intestine were removed. The small intestine was divided into 3 parts. Total mRNA was extracted from samples of these specimens, and cDNA was synthesized by quantitative real-time polymerase chain reaction (RT-PCR) using specific primers for each ugt gene. The ugt1a9 mRNA level was reduced by 2.25-fold in the liver and by 6-, 1.5-, and 3-folds in the first, second and third part of the small intestine, respectively. The ugt2b1 mRNA level in the liver and the third part of the small intestine was not affected, while it was reduced by 3.7- and 3-folds in the first and second parts of the small intestine, respectively. The ugt2a3 mRNA level was not affected in the liver and the 3 parts of the small intestine. Some ugt mRNA levels may be reduced by the ingestion of pomegranate juice, which may reduce the metabolism of their drug substrates. The consequences may be an accumulation of such drugs in the body and enhanced toxicity.