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BACKGROUND: A 76-year-old man was admitted to a local rehabilitation inpatient facility following an acute myocardial infarction. Patient history included hypertension and previous stroke. The patient was being treated with clopidogrel and aspirin for secondary stroke prevention along with other medications to treat hypertension. The patient admitted to using cannabidiol (CBD) oil up to three times a day for knee pain prior to acute myocardial infarction and requested to continue its use in the facility. ASSESSMENT: Prior to this hospital stay, the patient was able to continue activities of daily living with knee pain that was controlled by CBD oil used three times daily. The option to continue CBD oil would create a possible drug interaction with current cardiovascular medications leading to increased cardiovascular or bleeding risks. OUTCOME: The patient was advised against the use of CBD products because of potential interaction with clopidogrel and was prescribed acetaminophen for osteoarthritis (knee pain). The patient continued to improve and was discharged to his home after two weeks of rehabilitation. CONCLUSION: Based on limited pharmacodynamic and pharmacokinetic studies in older people, patients should avoid using cannabidiol and products containing its derivatives with P2Y12 inhibitors. A potential interaction between cannabidiol and its derivatives with P2Y12 inhibitors may increase a patient's cardiovascular or bleeding risks. Patients and health care providers must be adequately informed about potential risks associated with cannabidiol products and oral antiplatelets to prevent negative outcomes. [ABSTRACT FROM AUTHOR]

Favipiravir is one of the most used antiviral agents for the treatment of coronavirus disease 2019 infection in many countries, including Thailand. This study aimed to investigate the effect of favipiravir‐warfarin interaction in terms of changes in international normalized ratio (INR) of patients. Medication charts of all inpatients in a hospital in Thailand between April 2021 and March 2022 were reviewed. Patients who received either warfarin with standard care or warfarin with favipiravir were included. The INR levels of patients were monitored at baseline and the earliest date following treatment, as well as other laboratory parameters. There were 43 and 53 patients in the warfarin‐favipiravir and the warfarin‐only groups, respectively. Baseline characteristics, such as sex, age, body mass index, and warfarin dose, were not significantly different between the 2 groups. The results showed that the mean INR of patients using favipiravir and warfarin was increased from 2.14 to 3.88 (P <.001), while the patients using warfarin alone had no increase in the mean INR (1.93 vs 1.91; P =.906). Other parameters were not significantly changed, including white blood cell count, red blood cell count, hemoglobin, hematocrit, and liver function. However, an increase in platelet count was observed in the favipiravir‐warfarin group, but not in the control group. This real‐world study highlighted a significant increase in the INR levels of patients who used favipiravir together with warfarin, compared to patients who used only warfarin. However, the interaction did not affect other laboratory parameters, except an increase in platelet count. [ABSTRACT FROM AUTHOR]

Vatiquinone is a small‐molecule inhibitor of 15‐lipoxygenase in phase 3 development for patients with mitochondrial disease and Friedreich ataxia. The objective of this analysis was to determine the effect of vatiquinone on the pharmacokinetic profile of rosuvastatin, a breast cancer resistance protein substrate. In vitro investigations demonstrated potential inhibition of BCRP by vatiquinone (half maximal inhibitory concentration, 3.8 µM). An open‐label, fixed‐sequence drug‐drug interaction study in healthy volunteers was conducted to determine the clinical relevance of this finding. Subjects received a single dose of 20‐mg rosuvastatin followed by a 7‐day washout. On days 8 through 14, subjects received 400 mg of vatiquinone 3 times daily. On day 12, subjects concomitantly received a single dose of 20‐mg rosuvastatin. The geometric mean ratio for maximum plasma concentration was 77.8%; however, the rosuvastatin disposition phase appeared unaffected. The geometric mean ratios for the area under the plasma concentration–time curve from time 0 to time t and from time 0 to infinity were 103.2% and 99.9%, respectively. Mean rosuvastatin apparent elimination half‐life was similar between treatment groups. These results demonstrate that vatiquinone has no clinically relevant effect on the pharmacokinetics of rosuvastatin. [ABSTRACT FROM AUTHOR]

A lack of reliable information hinders the clinician evaluation of suspected herb–drug interactions. This pilot study was a survey-based study conceived as a descriptive analysis of real-life experiences with herb–drug interaction from the perspective of herbalists, licensed health-care providers, and lay persons. Reported dietary supplement–drug interactions were evaluated against the resources most commonly cited for the evaluation of potential supplement–drug interactions. Disproportionality analyses were performed using tools available to most clinicians using data from the U.S. Federal Adverse Event Reporting System (FAERS) and the US Center for Food Safety and Applied Nutrition (CFSAN) Adverse Event Reporting System (CAERS). Secondary aims of the study included exploration of the reasons for respondent use of dietary supplements and qualitative analysis of respondent's perceptions of dietary supplement–drug interaction. While agreement among reported supplement–drug interactions with commonly cited resources for supplement–drug interaction evaluation and via disproportionality analyses through FAERS was low, agreement using data from CAERS was high. [ABSTRACT FROM AUTHOR]

Disappointing results from the POLAR A and M phase III trials involving colorectal cancer patients on chemotherapy with FOLFOX6 in curative (A) and palliative (M) settings have been reported by the principal investigators and the sponsor (PledPharma AB/Egetis Therapeutics AB). FOLFOX6, oxaliplatin in combination with 5-fluorouracil (5-FU), possesses superior tumoricidal activity in comparison to 5-FU alone, but suffers seriously from dose-limiting platinum-associated Chemotherapy-Induced Peripheral Neuropathy (CIPN). The aim of the POLAR trials was to demonstrate that PledOx [calmangafodipir; Ca4Mn(DPDP)5] reduced the incidence of persistent CIPN from 40% to 20%. However, this assumption was based on "explorative" data in the preceding PLIANT phase II trial, which did not mirror the expected incidence of unwanted toxicity in placebo patients. In POLAR A and M, the assessment of PledOx efficacy was conducted in patients that received at least six cycles of FOLFOX6, enabling analyses of efficacy in 239 A and 88 M patients. Instead of a hypothesized improvement from 40% to 20% incidence of persistent CIPN in the PledOx group, i.e., a 50% improvement, the real outcome was the opposite, i.e., an about 50% worsening in this bothersome toxicity. Mechanisms that may explain the disastrous outcome, with a statistically significant number of patients being seriously injured after having received PledOx, indicate interactions between two redox active metal cations, Pt2+ (oxaliplatin) and Mn2+ (PledOx). A far from surprising causal relationship that escaped prior detection by the study group and the sponsor. Most importantly, recently published data (ref 1) unequivocally indicate that the PLIANT study was not suited to base clinical phase III studies on. In conclusion, the POLAR and PLIANT trials show that PledOx and related manganese-containing compounds are unsuited for co-treatment with platinum-containing compounds. For use as a therapeutic adjunct in rescue treatment, like in ischemia-reperfusion of the heart or other organs, or in acetaminophen (paracetamol)-associated liver failure, there is little or nothing speaking against the use of PledOx or other PLED compounds. However, this must be thoroughly documented in more carefully designed clinical trials. [ABSTRACT FROM AUTHOR]

Key Clinical Message Serotonin syndrome can be a life‐threatening condition that occurs from the overactivity of serotonin in the central nervous system. This report describes the use of cyproheptadine for the management of serotonin syndrome in a patient taking fluoxetine and bupropion, who received methylene blue for vasoplegia syndrome. A 61‐year‐old female taking fluoxetine and bupropion preoperatively was given a total of three doses of methylene blue 100 mg IV within a brief time frame during and after a planned coronary artery bypass graft surgery. Postoperatively, the patient was not following commands, was agitated and confused, febrile with diaphoresis, tachycardic, had muscle rigidity, and horizontal ocular clonus. The patient's presentation was most consistent with serotonin syndrome due to a drug–drug interaction. Cyproheptadine and supportive care were used successfully to treat serotonin syndrome, and the patient was discharged home 14 days postoperatively. Based on the literature, there is no standardized method of weaning cyproheptadine when used for serotonin syndrome. The patient in our case received a total of 188 mg of cyproheptadine over the course of 10 days and did not experience any side effects. This case highlights a potential dosing regimen that can be used for other patients.

Torsemide is commonly used to relieve edema during the treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO). We explored the effect of torsemide on the plasma concentrations of inorganic arsenic (iAs), monomethylarsonic acid (MMAV) and dimethyarsinic acid (DMAV) in APL patients treated with ATO and clarified its molecular mechanism in rats and cells. The study included 146 APL patients treated with ATO. 60（41.1 %) of these 146 patients were co-administered with torsemide. The treatment of torsemide increased plasma concentrations of iAs (P

Polypharmacy is becoming increasingly prevalent in society. Patients with polypharmacy are at greater risk for drug-drug interactions, which can influence the efficacy of treatment. Especially, in oncology this is a concern since neoplasms are increasing prevalent with age, as well as polypharmacy is. Besides drug-drug interactions, also herb-drug and food-drug interactions could be present. Knowledge of these interactions is of great importance for safe and effective anti-cancer treatment, because the therapeutic window of most of these oncologic drugs are small. To study pharmacokinetic interaction effects, a cross-over pharmacokinetic study is a widely used, efficient and scientifically robust design. Yet, several aspects need to be considered when carrying out an interaction study. This includes the knowledge of the advantages and disadvantages of a cross-over design. Furthermore, determination of the end point and research question of interest, calculation of the required sample size, analysis of the generated data with a robust statistical plan and consideration of the logtransformation for some pharmacokinetic parameters are important aspects to consider. Even though some guidelines exist regarding these key issues, no clear overview exists. In this article an overview of these aspects is provided and their effect is discussed.

Regardless of the currently proposed best medical treatment for heart failure patients, the morbidity and mortality rates remain high. This is due to several reasons, including the interaction between oral cardiac drug administration and gut microbiota. The relation between drugs (especially antibiotics) and gut microbiota is well established, but it is also known that more than 24% of non-antibiotic drugs affect gut microbiota, altering the microbe’s environment and its metabolic products. Heart failure treatment lies mainly in the blockage of neuro-humoral hyper-activation. There is debate as to whether the administration of heart-failure-specific drugs can totally block this hyper-activation, or whether the so-called intestinal dysbiosis that is commonly observed in this group of patients can affect their action. Although there are several reports indicating a strong relation between drug–gut microbiota interplay, little is known about this relation to oral cardiac drugs in chronic heart failure. In this review, we review the contemporary data on a topic that is in its infancy. We aim to produce scientific thoughts and questions and provide reasoning for further clinical investigation.

Drug repurposing is a strategy for discovering new applications of existing drugs for use in various diseases. Despite the use of structured networks in drug research, it is still unclear how drugs interact with one another or with genes. Prostate adenocarcinoma is the second leading cause of cancer mortality in the United States, with an estimated incidence of 288,300 new cases and 34,700 deaths in 2023. In our study, we used integrative information from genes, pathways, and drugs for machine learning methods such as clustering, feature selection, and enrichment pathway analysis. We investigated how drugs affect drugs and how drugs affect genes in human pancreatic cancer cell lines that were derived from bone metastases of grade IV prostate cancer. Finally, we identified significant drug interactions within or between clusters, such as estradiol-rosiglitazone, estradiol-diclofenac, troglitazone-rosiglitazone, celecoxib-rofecoxib, celecoxib-diclofenac, and sodium phenylbutyrate-valproic acid.

Abstract Background Muscarinic agonists are indicated for the treatment of many conditions including ileus, urinary retention, glaucoma, and Sjögren’s syndrome. Due to their lack of tissue specificity, these drugs can lead to undesirable side effects at off-target sites and may be potentiated by supplements that impact the half-life of these drugs. Case presentation A 58-year-old Caucasian female with history of Sjögren’s syndrome, who was being managed with cevimeline, presented to the primary care office with reported hyperhidrosis, malaise, nausea, and tachycardia. She reported taking an herbal supplement containing B. monnieri and phosphatidylserine the previous night. It has been previously demonstrated that B. monnieri alters cytochrome P450 enzymes. Electrocardiogram showed no acute ST–T changes. Clinical improvement occurred with hydration and discontinuation of the supplement. Conclusions To our knowledge, there has only been one other documented cevimeline overdose, and it was not associated with an herbal supplementation interaction. Physicians should actively elicit herbal supplement information from patients to anticipate possible drug–herb interactions. An additional consideration of clinical relevance is the known genetic variability that may affect drug responsiveness due to differences in metabolism and half-life of drugs that arise from common genetic variants of cytochrome P450 genes.

Purpose To describe a case report of antiretroviral regimen selection, with considerations for drug-supplement interactions, for a patient living with HIV with complicated nutrition needs. Summary A 56-year-old white female with a history of sleeve gastrectomy was initiated on coformulated bictegravir/emtricitabine/tenofovir alafenamide for treatment of HIV infection. Her baseline HIV viral load was 139,790 RNA copies/mL, and the baseline CD4 cell count was 544 cells/mm3. The patient additionally had a nutritional supplement regimen of twice-daily calcium and twice-daily multivitamins with minerals following sleeve gastrectomy. Due to binding interactions between polyvalent cations and bictegravir and the potential impact on antiretroviral efficacy, construction of a daily medication schedule to avoid interactions between the antiretroviral regimen and the supplements while promoting optimal dosing of each supplement was necessary; however there is currently no guidance on twice-daily cation dosing with coadministered bictegravir and limited guidance on multivitamin coadministration in this context. A review of the available literature on bictegravir interactions and pharmacokinetic parameters was performed. A dose separation strategy was utilized to design a regimen that maximized separation of doses of supplements from doses of bictegravir/emtricitabine/tenofovir alafenamide while minimizing interaction potential. At follow-up 8 weeks after regimen initiation, the HIV viral load was undetectable (<40 copies/mL) and the CD4 cell count had increased to 821 cells/mm3. Conclusion Integrase strand transferase inhibitor interactions with polyvalent cations in nutritional supplements can be avoided or mitigated with attention to timing of each dose and optimizing separation strategies. This case report shows the potential for alleviating such interactions through optimal dose scheduling. [ABSTRACT FROM AUTHOR]

Adverse interactions between intravenous medications which are given simultaneously are a common problem in intensive care medicine. They are usually caused by administering a high number of medications over a limited number of intravenous lines or central venous catheters; however, this issue also arises in routine anesthetic procedures during surgery. The following case report highlights a so far undocumented interaction between the combination of theodrenaline/cafedrine and various antibiotics. Laparoscopic cholecystectomy was performed in a female patient, classified as ASA 1. After induction of general anesthesia 2 g ceftriaxone were administered as a perioperative antibiotic prophylaxis. Simultaneously, i.e. prior to the beginning of surgery, a mild decrease in blood pressure was observed and 2 ml diluted Akrinor® (2 ml theodrenaline/cafedrine + 8 ml NaCl 0.9%) was administered. Directly following this administration a chemical precipitation reaction occurred, and large white pasty flakes were noticed in the intravenous line. The infusion was stopped immediately and all lines were replaced. In order to confirm a causal relationship between the observed precipitation and the simultaneous administration of the two drugs, an in vitro test was performed by mixing Akrinor® with other preparations of cephalosporin antibiotics. The effect observed with ceftriaxone was reproducible and cefazoline also caused a precipitation reaction. [ABSTRACT FROM AUTHOR]

This study evaluated possible interaction between Ayurvedic anti-urolithiac agent hydroalcoholic extract of Didymocarpus pedicellata (HADP) leaves and gliclazide. Dose optimization performed by measuring serum glucose levels after 200 and 400 mg/kg HADP administration to normal rats. Pharmacokinetic interaction study in normal rats performed by administration of gliclazide alone and combination with HADP (400 mg/kg). Diabetes was induced by administration of streptozotocin (55 mg/kg) and animals were treated with gliclazide, HADP and combination for 28 days. Pharmacokinetic and dynamic interaction were assessed after single (day 1) and repeated dose (day 28) co-administration by determination of serum gliclazide and glucose levels respectively. Gliclazide showed biphasic concentration time data and glucose reduction with maximum reduction at 2 and 8h post administration. HADP showed dose proportionate hypoglycemic effect in normal rats, hence 400 mg/kg was used for further studies. There was significantly higher decrease in percentage reduction of glucose levels in co-administration group as compared to gliclazide only group in normal, diabetic rats after single and repeated administration. Reduction was higher in repeated administration as compared to single. There was a non-significant increase in pharmacokinetic parameters in normal and diabetic rats after single HADP administration. Repeated HADP administration in diabetic rats caused significant increase in all pharmacokinetic parameters of gliclazide. On day 28 biochemical parameters are estimated to evaluate effect on oral administration of HADP with gliclazide for 28 days to diabetic animals. The results are shown a significant improvement in dyslipidemia, triglyceride levels and liver functional parameters such as SGOT, SGPT, ALP, and total protein in HADP combination as compared to the vehicle control group. Combination of gliclazide and HADP showed a significant pharmacodynamic and pharmacokinetic interaction with gliclazide. Hence precautions has to be observed in co-administration of gliclazide with HADP and dosage adjustments of gliclazide might be required in a clinical setting to avoid sever hypoglycemia. [ABSTRACT FROM AUTHOR]

Purpose In the pediatric population, warfarin remains the recommended oral anticoagulant for valvular heart disease. Warfarin carries a risk of bleeding complications that can manifest as heavy menstrual bleeding (HMB) in postmenarchal adolescent females. As a result, these patients may be started on hormonal therapies, such as norethindrone, to suppress menstruation. Summary This case series describes a potential drug interaction between warfarin and norethindrone in 3 adolescent females with a history of mechanical mitral valve replacement who developed HMB. These patients were on stable warfarin regimens before the initiation of norethindrone and subsequently experienced increases in their international normalized ratio (INR). In response, they required an up to 50% reduction in their weekly warfarin dose over 5 to 12 weeks. Conclusion These observations suggest that use of norethindrone for the management of HMB may significantly potentiate the anticoagulant effect of warfarin. Close INR monitoring and aggressive dose adjustments during initiation and discontinuation of norethindrone are recommended in patients on warfarin. [ABSTRACT FROM AUTHOR]

The interaction of two or more drugs may compromise safety and efficacy, cause adverse reactions, or enhance the therapeutic effect. Oral contraceptives are the most effective contraception used by thousands of women. Antibiotics are used in bacterial diseases that have been considered incurable or even lethal for a long time. The effect of the interaction between these drugs remains controversial. This study aimed to conduct a survey with 201 women between 17 and 48 years of age from different undergraduate courses. A questionnaire verified their knowledge about contraceptives and antibiotics and whether they knew the possible interactions. 78% of these women knew the possibility of an interaction between these drugs. Women reported two unplanned pregnancies with no medical or pharmaceutical explanation of the likelihood of interaction. Health education and additional birth control are significant measures during and after antibiotic therapy. In addition, the use of probiotics with the concomitant use of antibiotics and contraceptives is indicated. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the application of Danhong injection in inpatient prescriptions of the hospital, and to provide reference for clinical medication, so as to improve the quality of prescription and safety and effectiveness of medication. METHODS: From Jan. 2018 to Feb. 2022, 68 211 inpatient prescriptions of Danhong injection were extracted from the information system of the hospital. The prescription analysis system PA 2. 1 independently developed by the hospital was used to perform special review on basic prescription information, clinical diagnosis and drug combination. RESULTS: Of the 68 211 prescriptions of Danhong injection, there were 3 038 inappropriate prescriptions (4. 45%), mainly for repeated medication prescriptions (3 018 prescriptions, 4. 42%) and incompatible prescriptions (20 prescriptions, 0. 03%). There were 5 097 potential risk prescriptions (7. 47%), mainly reflected in potential drug interactions. CONCLUSIONS: The application of Danhong injection in the hospital is basically reasonable, yet the problems such as repeated medication and incompatibility should be prevented. Meanwhile, attention should be paid to the pharmaceutical care when Danhong injection is used in combination with high-risk drugs to promote rational drug use. [ABSTRACT FROM AUTHOR]

Background: Epilobium parviflorum (Schreb.) Schreb. has been used traditionally to treat prostate, bladder and kidney diseases, as well as inflammation. However, E. parviflorum extracts are yet to be tested for the ability to inhibit the growth of bacterial triggers of autoimmune diseases. Materials and Methods: Antimicrobial activity was assessed using disc diffusion and liquid dilution minimum inhibitory concentration (MIC) assays against a panel of bacterial triggers of some autoimmune diseases. Interactions between the E. parviflorum extracts and conventional antibiotics were studied and classified using the sum of the fractional inhibitory concentration (∑FIC). Notable synergistic interactions were further examined across a range of ratios using isobologram analysis. The toxicity of the individual samples and the combinations was assessed using the Artemia lethality assay (ALA) assay. Results: Epilobium parviflorum extracts displayed notable antibacterial activity against the bacterial trigger of rheumatoid arthritis (P. mirabilis), but were ineffective against K. pneumoniae, A. baylyi, P. aeruginosa and S. pyogenes. The methanolic and ethyl acetate extracts were particularly good inhibitors of P. mirabilis growth, with MIC values of 484 and 623µg/mL recorded respectively. Furthermore, combining the extracts with conventional antibiotics resulted in significant potentiation of the inhibitory activity for some combinations. Interestingly, all combinations containing chloramphenicol or ciprofloxacin produced either synergistic or additive effects against P. mirabilis. None of the individual components (nor the combinations) were toxic in the ALA assay. Conclusion: The E. parviflorum methanolic and ethyl acetate extracts displayed clinically relevant antibacterial activity against P. mirabilis when tested alone. Furthermore, the methanolic and aqueous extracts potentiated the activity of chloramphenicol and ciprofloxacin in combination. The lack of toxicity of the extract and combinations indicates that E. parviflorum methanolic and aqueous extract and antibiotic combinations may provide leads in the development of new therapies to prevent and treat rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase (CDK) 4/6 inhibitors given with endocrine therapy are standard of care for the treatment of women with advanced hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER-2) negative breast cancer. Ribociclib is a CDK 4/6 inhibitor with moderate to solid inhibition of CYP3A4, a member of the cytochrome P450 family oxidase system, which may lead to interactions with medicinal substrates that are metabolized via CYP3A4. Statins are among the most widely prescribed medications worldwide, predominantly metabolized by the CYP3A4 isoenzyme. Rhabdomyolysis is a known rare side effect of statins, commonly triggered by drug interactions. We report a case of a 73-year-old woman with metastatic HR-positive and HER-2 negative breast cancer who developed rhabdomyolysis and acute kidney injury due to interaction between simvastatin and ribociclib with a literature review. [ABSTRACT FROM AUTHOR]

Background Direct oral anticoagulants (DOACs) are useful for stroke prevention in atrial fibrillation (AF) patients. However, the concomitant administration of Levetiracetam limited their use in clinical practice, although some authors raise doubts about clinical relevance of the interaction. Case summary We report a case of a 54-year-old male with AF, cirrhosis, and seizures, in which the assessment of Dabigatran plasma concentration was needed due to the concomitant use of Levetiracetam. In this case, no relevant reduction of trough Dabigatran plasma concentration was found. An increased peak serum level of dabigatran may be obtained delaying levetiracetam administration. The patient was then followed in our clinic and during 32 months of follow-up no ischaemic or haemorrhagic events occurred. Discussion The evaluation of DOACs concentration could be helpful to start a tailored therapy in frailty patients. [ABSTRACT FROM AUTHOR]

Tacrolimus is an immunosuppressant with a narrow therapeutic window. Tacrolimus exposure increased significantly during voriconazole co-therapy. The magnitude of this interaction is highly variable, but it is hard to predict quantitatively. We conducted a study on 91 kidney transplantation recipients with voriconazole co-therapy. Furthermore, 1701 tacrolimus concentration data were collected. Standard concentration adjusted by tacrolimus daily dose (C/D) and weight-adjusted standard concentration (CDW) increased to 6 times higher during voriconazole co-therapy. C/D and CDW increased with voriconazole concentration. Patients with the genotype of CYP3A5 *3/*3 and CYP2C19 *2/*2 or *2/*3 were more variable at the same voriconazole concentration level. The final prediction model could explain 54.27% of the variation in C/D and 51.11% of the variation in CDW. In conclusion, voriconazole was the main factor causing C/D and CDW variation, and the effect intensity should be quantitative by its concentration. Kidney transplant recipients with CYP3A5 genotype of *3/*3 and CYP2C19 genotype of *2/*2 and *2/*3 should be given more attention during voriconazole co-therapy. The prediction model established in this study may help to reduce the occurrence of rejection. [ABSTRACT FROM AUTHOR]

(1) Background: With the massive demand for the use and commercialization of medicinal cannabidiol (CBD) products, new randomized clinical trials (RCTs) are being published worldwide, with a constant need for safety and efficacy evaluation. (2) Methods: We performed an update on a systematic review published in 2020 that focused on analyzing the serious adverse effects (SAEs) of CBD in RCTs and its possible association with drug interactions. We also updated the report of the most prevalent CBD adverse effects (AEs). We systematically searched EMBASE, MEDLINE/PubMed, and Web of Science without language restriction for RCTs that reported adverse effects after repeated oral CBD administration for at least one week in healthy volunteers or clinical samples published from January 2019 to May 2022. The included studies were assessed for methodological quality by the Quality Assessment of Controlled Intervention Studies tool. The present review is registered on PROSPERO, number CRD42022334399. (3) Results: Twelve studies involving 745 randomized subjects analyzed were included (range 1.1–56.8 y). A total of 454 participants used CBD in the trials. The most common AEs of CBD were mild or moderate and included gastrointestinal symptoms (59.5%), somnolence (16.7%), loss of appetite (16.5%), and hypertransaminasemia (ALT/AST) (12.8%). Serious adverse effects include mainly hypertransaminasemia with serum levels elevations greater than three times the upper limit of the normal (6.4%), seizures (1.3%), and rash (1.1%). All SAEs reported in the studies were observed on CBD as an add-on therapy to anticonvulsant medications, including clobazam and valproate. (4) Conclusion: Recent RCTs involving oral CBD administration for at least a week suggest that CBD has a good safety and tolerability profile, confirming previous data. However, it can potentially interact with other drugs and its use should be monitored, especially at the beginning of treatment. [ABSTRACT FROM AUTHOR]

Purpose: To describe a potential drug interaction between warfarin and the combination of remdesivir with dexamethasone. Summary: Two male patients, a 71-year-old and 62-year-old presented to the emergency department for symptoms of coronavirus disease 2019 (COVID-19). Both patients were on long-term warfarin therapy with their most recent international normalized ratio (INR) prior to admission within their patient specific goal as managed by their outpatient Pharmacist. In both instances, the patients denied any changes in diet, lifestyle, or missed doses of medications upon admission interview. During admission, both patients experienced a marked elevation in INR within 24 to 48 hours of the initiation of remdesivir with dexamethasone for COVID-19 pneumonia directed therapy. The patients were both eventually stable and were instructed to continue warfarin monitoring and management under the direction of their outpatient Pharmacist upon discharge. Conclusion: The underrecognized but probable interaction between warfarin in conjunction with remdesivir and dexamethasone warrants further analysis. [ABSTRACT FROM AUTHOR]

Statement of the Problem: Given the increase in the population of the elderly patients and the risk of systemic diseases in these individuals, the prevalence of the intake of various drugs is higher in elderly patients, which exposes them to the side effects of drugs including potential drug-drug interactions (DDIs). Purpose: Therefore, the present study is an attempt to evaluate the drug interactions between the drugs used by the elderly patients visiting Kerman School of Dentistry and the common dental drugs in 2020. Materials and Method: This cross-sectional study was conducted on the elderly patients (≥60‎years( who referred to Kerman School of Dentistry for dental problems. After obtaining the oral informed consent and collecting demographic information, the drugs used by the patients and their systemic diseases were questioned, listed, and compared with the drugs mentioned in their files. The drug interactions with the common dental drugs were studied in the elderly patients using the www.drugs.com website. Chi-square, T, ANOVA, KruskalWallis, and Mann-Whitney tests were used to compare the variables. The significance level was 0.05. Results: Of participants included in this study, 78 (52%) were female and 72(48%) were male. The average age of these patients was 71.27 6.32 years. The most common systemic diseases were hypertension (57.3%), heart diseases (42.0%), and diabetes mellitus (40.7%). Our analysis of the DDIs between 11 commonly prescribed dental drugs and 95 drugs used by the patients revealed 212 DDIs (21.7% minor, 68.3% moderate, and 9.9% major interactions). There was a significant relationship between the number of drugs and DDIs, whereas DDIs had no significant relationship with gender and educational level. Conclusion: The results reflected the high percentage of DDIs among the patients. In addition, there was a significant relationship between polypharmacy, which is highly prevalent among the elderly patients, and drug interactions. [ABSTRACT FROM AUTHOR]

Background: Olanzapine is used to treat schizophrenia and bipolar disorder in women of childbearing age. Continuation of psychotropic medications throughout pregnancy and lactation is often required as cessation could be dangerous for both mother and child. However, there is a lack of information on the transfer of these drugs into the developing brain. Methods: Sprague Dawley rats at three developmental ages: embryonic day E19, postnatal day P4 and non-pregnant adult females were administered unlabelled or radiolabelled ( 3H) olanzapine (0.15 mg/kg) either as monotherapy or in combination with each of seven other common medications. Similar injections were administered to pregnant E19 females to investigate placental transfer. Olanzapine in plasma, cerebrospinal fluid (CSF) and brain was measured by liquid scintillation counting after a single dose (acute) or following 5 days of treatment (prolonged). Results: Olanzapine entry into brain and CSF was not age-dependent. Prolonged olanzapine treatment reduced placental transfer from 53% to 46% (p Conclusions: Co-administration of olanzapine with some commonly used drugs affected its entry into the fetus and its developing brain to a greater extent than in adults. It appears that protection of the fetal brain for these drugs primarily comes from the placenta rather than from the fetal brain barriers. Results suggest that drug combinations should be used with caution particularly during pregnancy.

Perioperative hyperthermia has many differential diagnoses. This case report describes the rare causation of perioperative hyperthermia in a patient presenting for epilepsy surgery. The patient had two episodes of hyperthermia, initially post-anesthetic induction and later in the immediate post-operative period. The quest for the etiology sheds light on a rare drug interaction between topiramate, an antiepileptic drug, and glycopyrrolate causing intraoperative hyperthermia. However, the literature has not reported drug interaction between topiramate and glycopyrrolate resulting in perioperative hyperthermia. The combination of a glycopyrrolate-induced rise in temperature and oligohidrosis could have resulted in hyperthermia in our patient. Thus, it is prudent to avoid glycopyrrolate in the perioperative period when patients are on topiramate.

Background. The endogenous opioid system is involved in neuroadaptation produced by exogenous opioids. Synthesized on the basis of the regulatory peptide tuftsin, the anxiolytic selank inhibits the activity of enkephalin-degrading enzymes, increasing the level of leu-enkephalins in blood plasma. The aim of the work was to evaluate the effect of selank (0,3 and 0,9 mg/kg, i. p.) on morphine-induced analgesia in animal models. Methods. The experiments were performed in inbred male mice C57Bl/6 (n = 77). The “hot plate” test was used to evaluate the analgesic effect during thermal stimulation of nociceptors when mice were placed on a metal plate heated to 55 ± 0,5 °C, followed by registration of the latent period of the reaction 30, 60, 90, and 120 minutes after the administration of morphine. Results. Morphine at a dose of 3,0 mg/kg, i. p., caused antinociception with the maximum possible effect (MBE) of 9 %, selank at a dose of 0,9 mg/kg, without antinociception per se, when pretreated with the morphine, increased the latent reaction time, causing antinociception of 29,9 % MBE. Conclusion. For the first time the data obtained on the synergistic effect of selank and morphine in attenuation of acute somatic pain.

Limi Adem, Gobezie T Tegegne Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Science, Addis Ababa University, Addis Ababa, EthiopiaCorrespondence: Gobezie T Tegegne, Email gobezie.temesgen@aau.edu.etBackground: Appropriate prescribing is often challenging in geriatric patients due to age-related pharmacokinetic and pharmacodynamic alterations. Elderly patients with cardiovascular diseases are frequently prescribed multiple medications. Hence, it is imperative to investigate medication appropriateness, polypharmacy, and drug-drug interactions in these groups of patients.Objective: To assess medication appropriateness using the 2019 American Geriatric Society Beers and Medication Appropriateness Index criteria, polypharmacy and drug-drug interactions among elderly ambulatory patients with cardiovascular diseases at Tikur Anbessa Specialized Hospital.Methods: A hospital-based retrospective cross-sectional study was conducted among 384 elderly (60 years and older) ambulatory patients with cardiovascular diseases between May 01-August 30, 2021. Data was collected from the patient’s medical record using a data abstraction tool. The data were entered and analyzed using the SPSS program. Descriptive and logistic regression models were used to present the findings.Results: The most frequent diagnosis was hypertension (78.4%) followed by ischemic heart disease (31.3%). Averagely, 4.4 ± 2 medications were prescribed per patient. More than half of (53.1%) the patients received polypharmacy. According to Beer’s and medication appropriateness index criteria, over one-third (28.1%) and the majority (95.1%) of the patients were prescribed potentially inappropriate medications, respectively. In addition, 53.1% and 90.1% of patients had polypharmacy, and were exposed to potential drug-drug interactions ranging from mild to major interactions, respectively. Further, polypharmacy was significantly associated with inappropriate medication prescribing.Conclusion: The study found that more than half of the patients got one or more potentially inappropriate medications in both criteria. The medication appropriateness index tool identified more potentially inappropriate medication than the Beers criteria. In addition, more than half of the patients got polypharmacy and had potential drug-drug interactions. Further, polypharmacy was significantly associated with inappropriate medication prescriptions. These findings highlight the need for interventions to improve appropriate prescribing practice among elderly patients.Keywords: inappropriate medication, polypharmacy, drug interaction, cardiovascular disease and elderly

[Display omitted] • Commercial precoated PAMPA is the most sensitive system for evaluating excipient effects. • PermeaPadTM is applicable to highly cytotoxic excipients owing to its high tolerance to excipient concentrations. • Caco-2 is a robust cell line that can be used to evaluate excipients at relatively high concentrations. • Most evaluated excipients did not affect drug membrane permeation at clinically used concentrations. The effects of pharmaceutical excipients on intestinal drug absorption have been highlighted and careful excipient selection is required to develop biologically equivalent formulations. This study aimed to evaluate the effects of excipients on drug permeability and compare the characteristics of in vitro screening methods. Three in vitro models, the commercial precoated parallel artificial membrane permeability assay (PAMPA), PermeaPadTM, and Caco-2 monolayer, were used to evaluate the effects of 14 excipients on the permeability of several drugs with different biopharmaceutical classification system classes. Concentration-dependent effects were analyzed to distinguish non-specific effects. The permeability of low-permeability drugs was increased by excipients such as hydroxypropyl cellulose and povidone K30 in the precoated PAMPA model, whereas PermeaPadTM maintained membrane integrity at higher concentrations. Conversely, croscarmellose sodium and sodium lauryl sulfate (SLS) decreased the permeability of highly permeable drugs in both precoated PAMPA and PermeaPadTM assays in a concentration-dependent manner. In Caco-2 monolayer assays, most excipients showed minimal effects on drug permeability. However, SLS significantly reduces the permeability of highly permeable drugs at concentrations above the critical micelle concentration, thereby compromising the integrity of the cell monolayer. Our results suggested that most of excipients, except SLS, did not affect the membrane permeation of drugs at clinically used concentrations. The pre-coated PAMPA model demonstrated high sensitivity to excipient effects, making it suitable for conservative evaluation. The PermeaPadTM and Caco-2 models allowed assessment at higher excipient concentrations, with PermeaPadTM being particularly useful for excipients that cause toxicity in Caco-2 cells. [ABSTRACT FROM AUTHOR]

Sunitinib, a novel anti-tumor small molecule targeting VEGFR, is prescribed for advanced RCC and GISTs. Sunitinib is primarily metabolized by the CYP3A enzyme. It is well-known that dexamethasone serves as a potent inducer of this enzyme system. Nonetheless, the effect of dexamethasone on sunitinib metabolism remains unclear. This study examined the effect of dexamethasone on the pharmacokinetics of sunitinib and its metabolite N-desethyl sunitinib in rats. The plasma levels of both compounds were measured using UHPLC-MS/MS. Pharmacokinetic parameters and metabolite ratio values were calculated. Compare to control group, the low-dose dexamethasone group and high-dose dexamethasone group decreased the AUC (0-t) values of sunitinib by 47 % and 45 %, respectively. Meanwhile, the AUC (0-t) values of N-desethyl sunitinib were increased by 2.2-fold and 2.4-fold in low-dose dexamethasone group and high-dose dexamethasone group, respectively. The CL values for sunitinib were both approximately 45 % higher in the two dexamethasone groups. Remarkably, metabolite ratio values increased over 5-fold in both low-dose dexamethasone group and high-dose dexamethasone group, indicating a significant enhancement of sunitinib metabolism by dexamethasone. Moreover, the total levels of sunitinib and its metabolite are also significantly increased. The impact of interactions on sunitinib metabolism, as observed with CYP3A inducers such as dexamethasone, is a crucial consideration for clinical practice. To optimize the dosage and prevent adverse drug events, therapeutic drug monitoring can be employed to avoid the toxicity from such interactions. • The CYP3A inducer dexamethasone altered the pharmacokinetics of sunitinib and its metabolite in rat. • Both the low-dose and high-dose dexamethasone increased the metabolism of sunitinib. • Dexamethasone significantly increased the total levels of sunitinib and its metabolite. [ABSTRACT FROM AUTHOR]

This work explored the influence of cuminaldehyde on the metabolic activity of four primary human cytochrome P450 (CYP) enzymes. Human liver microsomes (HLM) with and without cuminaldehyde were incubated with specific substrates of different CYP enzymes. The influence of cuminaldehyde on "CYP1A2, CYP2C9, CYP2D6 and CYP3A4" activities was examined. The formation of specific metabolites was analyzed by HPLC analytical methods. It was observed that cuminaldehyde appears to have a negligible influence on CYP1A2 activity. However, CYP2C9 activity was significantly and potently inhibited by cuminaldehyde at all investigated concentrations. It was found that cuminaldehyde (1 µM) inhibited the most CYP2C9 enzyme activity with 64.87 % inhibition followed by CYP3A4 (38.90 %), CYP2D6 (25.76 %) and CYP1A2 (4.99 %). Inhibition of both CYP2D6 and CYP3A4 enzyme activity was observed in response to cuminaldehyde concentrations. Findings of the current investigation indicate that herb-drug interactions are very possible when cuminaldehyde is concurrently taken with medicines predominantly metabolized by CYP2C9 and CYP3A4. Cuminaldehyde should be tested further to examine how it affects CYP2C9 and CYP3A4-metabolized drugs. [ABSTRACT FROM AUTHOR]

The adsorption of pyrazinamide (PZA) drug by the assistance of FeC 20 , FeC 19 , and FeC 18 iron-decorated metallofullerenes were analyzed using density functional theory (DFT) calculations regarding the drug delivery developmental issues. Formations of PZA@FeC 20 , PZA@FeC 19 , and PZA@FeC 18 conjugated systems were analyzed by the structural and electronic features. Meaningful adsorption strengths were found for the models with a priority of PZA@FeC 20 conjugation formation with an exterior iron atom of the metallofullerene. Three configurations were found for each conjugation mainly along with the existence of O...Fe and O...N interactions and a complementary H...C interaction. Hence, the conjugated systems could show a suitable "recovery time" for providing the sensing function along with the changes of "conductance rate" levels. Indeed, the results indicated the formation of observable conjugated systems, in which the conjugations and configurations could be employed regarding a customization towards the drug delivery of PZA antibiotic in a smart mode. [ABSTRACT FROM AUTHOR]

Background: Olanzapine is used to treat schizophrenia and bipolar disorder in women of childbearing age. Continuation of psychotropic medications throughout pregnancy and lactation is often required as cessation could be dangerous for both mother and child. However, there is a lack of information on the transfer of these drugs into the developing brain. Methods: Sprague Dawley rats at three developmental ages: embryonic day E19, postnatal day P4 and non-pregnant adult females were administered unlabelled or radiolabelled ( 3H) olanzapine (0.15 mg/kg) either as monotherapy or in combination with each of seven other common medications. Similar injections were administered to pregnant E19 females to investigate placental transfer. Olanzapine in plasma, cerebrospinal fluid (CSF) and brain was measured by liquid scintillation counting after a single dose (acute) or following 5 days of treatment (prolonged). Results: Olanzapine entry into brain and CSF was not age-dependent. Prolonged olanzapine treatment reduced placental transfer from 53% to 46% (p Conclusions: Co-administration of olanzapine with some commonly used drugs affected its entry into the fetus and its developing brain to a greater extent than in adults. It appears that protection of the fetal brain for these drugs primarily comes from the placenta rather than from the fetal brain barriers. Results suggest that drug combinations should be used with caution particularly during pregnancy.

Linezolid (LZD) has a longstanding reported association with the onset of serotonin toxicity (ST), secondary to drug–drug interactions with serotoninergic agents. There have been no conclusive data supporting the incidence or contributing risk factors to date. The study evaluated the incidence of ST in patients treated with LZD and serotonergic agents concomitantly versus LZD alone. The secondary objectives included a comparison of ST incidence in patients treated with one serotonergic agent + LZD versus two or more serotonergic agents + LZD. The studies used for this meta-analysis were retrieved from PubMed, Scopus, and Google Scholar. All studies including a comparison between LZD alone and LZD + a serotonergic agent published between 1 January 2000 and 1 October 2023 and meeting the quality standards were considered for inclusion. Fourteen studies were identified, with five meeting all inclusion and exclusion criteria with no significant heterogeneity. For the analysis of LZD monotherapy vs. SA combination therapy, four studies with 6025 patients total were analyzed and yielded an odds ratio of 1.78 (CI [1.04, 3.02]; I2 = 49%; GRADE certainty: low). Four studies and 2501 patients were included in the analysis of one versus more than one SA with an odds ratio of 5.18 (CI [1.05, 25.49]; I2 = 44.87; GRADE certainty: moderate). The Newcastle–Ottawa score, visual inspection of the funnel plot, and Egger’s statistic were used to evaluate quality and heterogeneity. The Peto method was used to calculate the summary odds ratios. All analyses were performed using Comprehensive Meta-Analysis version 3.0 and R, while GRADE was used to evaluate the quality of the final recommendation. The number of concomitant serotonergic agents may play a role in the development of serotonin toxicity in patients prescribed linezolid. In patients requiring linezolid therapy and serotonergic agents, risk versus benefit analysis should pay attention to the number of interacting drugs.

Abstract Background Voriconazole (VRCZ) is the first-line therapy for chronic pulmonary aspergillosis and is available in both intravenous and oral formulations. The bioavailability of the oral form is estimated to be over 90% in healthy volunteers. Some drugs are reported to interact with enteral nutrition (EN), but there are few reports about the trough levels of VRCZ during EN therapy. Here, we describe changes in the VRCZ trough levels in a patient receiving continuous EN therapy. Case presentation The patient was a 58-year-old man with esophageal cancer and a history of partial pulmonary resection due to aspergilloma. He was taking oral VRCZ tablets and his VRCZ trough level was about 2 μg/mL before esophageal cancer surgery. Following esophagectomy, VRCZ was restarted on postoperative day 16. Crushed VRCZ tablets were administered via a jejunostomy tube because of swallowing difficulty. He was also receiving EN, which was interrupted only during the administration of VRCZ. When we checked his VRCZ level 5 days after restarting VRCZ, the trough level was 0.80 μg/mL. After increasing the VRCZ dose, reducing EN, and changing the administration route from jejunostomy tube to oral, his trough level increased to 1.87 μg/mL. Conclusions A decrease in the VRCZ trough level was observed when VRCZ was administered via a jejunostomy tube while the patient was receiving continuous EN. Careful monitoring of VRCZ levels is needed in such cases.

Hyungsub Kim,1 Shi Hyang Lee,2 Jina Jung,3 Sunghee Hong,3 Hyeong-Seok Lim2 1Department of Emergency Medical Services, College of Health Sciences, Eulji University, Seongnam, Republic of Korea; 2Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; 3Hanmi Pharmaceutical Co. Ltd., Seoul, Republic of KoreaCorrespondence: Hyeong-Seok Lim, Tel +82-2-3010-4613, Fax +82-2-3010-4623, Email mdlhs@amc.seoul.krPurpose: The combined administration of tadalafil, a phosphodiesterase-5 inhibitor, and amlodipine, a calcium channel blocker, can be a promising therapeutic option for hypertension patients with erectile dysfunction. This study aimed to examine the pharmacokinetic drug interaction between tadalafil and amlodipine and the tolerability of their combined administration in healthy male subjects.Subjects and Methods: Healthy volunteers (N = 24) were randomly assigned to one of the six sequences that consisted of three treatments: tadalafil (5 mg) alone, amlodipine (10 mg) alone, and tadalafil plus amlodipine. The study drugs were administered orally for 9 d, and the collected serial blood samples were analyzed up to 72 h after the last dosing. Pharmacokinetic parameters were calculated using non-compartmental analysis.Results: For tadalafil, geometric mean ratios (GMRs) (90% confidence interval (CI)) of the combined therapy over the monotherapy were 1.57 (1.46– 1.68) for AUCτ,ss and 1.34 (1.24– 1.45) for Cmax,ss. For amlodipine, the GMRs (90% CI) of AUCτ,ss and Cmax,ss were 0.93 (0.90– 0.97) and 0.95 (0.91– 0.99), respectively. The severity of all observed adverse events (AEs) related to the study drugs was mild, and the frequency of AEs of the combined administration was not significantly different from the monotherapy.Conclusion: A substantial pharmacokinetic drug interaction between tadalafil and amlodipine was observed with respect to the concentration of tadalafil when administered concomitantly. However, the dose range of the combined administration of tadalafil and amlodipine in the present study was well tolerated by the subjects.Keywords: drug interaction, tadalafil, amlodipine, pharmacokinetics, tolerability

Abstract The study aimed to examine the effect of simultaneous application of florfenicol and lasalocid on the performance and vital organ function of chickens. For this, 300 chicks were divided into four groups. Group one to three received florfenicol, lasalocid and lasalocid plus florfenicol, respectively. Group four as the control group received a basic diet without lasalocid or florfenicol. Lasalocid was used from 7 to 35 days old, continuously. Florfenicol was used at 21 days old for 5 days. The growth indices were measured at the end of each week. The chickens were euthanized at the ages of 28 and 35 days old after collecting blood samples with and without anticoagulants. The liver, heart, muscle, kidney and sciatic nerve were collected in formalin 10% for histopathological examination. The blood and serum samples were used to determine clinical pathologic and hematologic indices. The ratio of internal organs to body weight and ratio of the right ventricle to the total ventricles (RV/TV) of the heart was measured. Results showed, the use of lasalocid decreased feed conversion rate and triglyceride, and increased total protein. Simultaneous administration of lasalocid and florfenicol affected histopathology of the liver and heart and significantly increased creatine phosphokinase, uric acid and the ratio of RV/TV of heart. The eosinophil percentage in the chickens who received florfenicol plus lasalocid was significantly higher than chickens who received florfenicol alone (p < 0.05). In conclusion, it seems that simultaneous administration of the florfenicol and lasalocid induces side‐effects especially on cardiac function and it is not recommended.

Abstract Background Azelnidipine, a dihydropyridine calcium channel blocker (CCB), has less adverse effects (e.g. hot flushes and reflex tachycardia) compared to other dihydropyridine CCBs. Azelnidipine has been reported to reduce heart rate as opposed to inducing tachycardia. No evidence of bradycardia or complete atrioventricular block (CAVB) with azelnidipine treatment has been reported. Case presentation In the present study, a 92-year-old woman was diagnosed with CAVB while taking azelnidipine and simvastatin for an extended period of time, and referred to our medical center. It was thought that the CAVB may have been an adverse effect of azelnidipine treatment. Specifically, it was considered that in this patient, one of the causes might be the concomitant use of simvastatin inhibiting the metabolism of azelnidipine by cytochrome P450 enzyme 3A4. Consequently, it was suggested to the patient’s physician that the patient’s serum azelnidipine levels be measured and treatment with azelnidipine and simvastatin be discontinued. The patient’s serum concentration of azelnidipine at the time of her visit to our center was 63.4 ng/mL, higher than the normal acceptable level. There was no occurrence of CAVB for 4 weeks, to present, following discontinuation of azelnidipine and simvastatin treatment. Conclusions Azelnidipine has a different mechanism of action that other CCBs. In very rare cases, it may cause CAVB when combined with CYP3A4 inhibitors. If a patient taking azelnidipine is diagnosed with CAVB, physicians should suspect that the condition may be an adverse effect of azelnidipine and should consider discontinuing azelnidipine. And, in the elderly, it is necessary to avoid concomitant use of CYP3A4 inhibitors.

Areca nut (AN) is consumed by millions of people for its therapeutic and psychoactive effects, making it one of the most widely self-administered psychoactive substances in the world. Even so, AN use/abuse is associated with myriad oral and systemic side effects, affecting most organ systems in the body. Alkaloids abundant in the nut (e.g. arecoline, arecaidine, guvacoline, and guvacine), collectively called the areca alkaloids, are presumably responsible for the major pharmacological effects experienced by users, with arecoline being the most abundant alkaloid with notable toxicological properties. However, the mechanisms of arecoline and other areca alkaloid elimination in humans remain poorly documented. Therefore, the purpose of this review is to provide an in-depth review of areca alkaloid pharmacokinetics (PK) in biological systems, and discuss mechanisms of metabolism by presenting information found in the literature. Also, the toxicological relevance of the known and purported metabolic steps will be reviewed. In brief, several areca alkaloids contain a labile methyl ester group and are susceptible to hydrolysis, although the human esterase responsible remains presumptive. Other notable mechanisms include N-oxidation, glutathionylation, nitrosamine conversion, and carbon–carbon double-bond reduction. These metabolic conversions result in toxic and sometimes less-toxic derivatives. Arecoline and arecaidine undergo extensive metabolism while far less is known about guvacine and guvacoline. Metabolism information may help predict drug interactions with human pharmaceuticals with overlapping elimination pathways. Altogether, this review provides a first-of-its-kind comprehensive analysis of AN alkaloid metabolism, adds perspective on new mechanisms of metabolism, and highlights the need for future metabolism work in the field. [ABSTRACT FROM AUTHOR]

• Chemical and biological characteristics of proteins and polyphenols result in changes in the properties of each other as well as health functionality. • Polyphenols-protein complexes cause the poor function of digestive enzymes. • tea consumption may interfere with the oral bioavailability or activity of some drugs through CYPs inhibition. Biological active compounds in tea such as phenolic compounds have become a focus of research due to their health-beneficial impacts on the human body as well as disease prevention. Moreover, these substances also have beneficial functions as they work as food preservatives. Polyphenols are known to form a complex with protein molecules leading to change in several properties. In this review, the effect of protein-polyphenol interaction on the structure, functionality, nutritional and digestive system as well as the inhibition activity of cytochrome 450 (CYP450) and drug interaction were described. Also, the chemical bonding, which discovered leading to precipitation and changes of protein structure were explained. The feasibility of proteins-polyphenols interaction cause associated with the ability on the digestive system whether enhance the enzymatic activity for digestion or a negative effect of the enzyme inhibition activity. As the bioactive compounds attracting consumer attention in recent years and they do not provide only an advantage side, therefore, it should be significantly studied what impacts to the human body these substances include which are helpful for further investigation. [ABSTRACT FROM AUTHOR]

Approximately 30% to 70% of patients with cirrhosis have QT interval prolongation. In patients without cirrhosis, QT prolongation is associated with an increased risk of ventricular arrhythmias, such as torsade de pointes (TdP). In cirrhotic patients, there is likely a significant association between the corrected QT (QTc) interval and the severity of liver disease, and possibly with increased mortality. We present a stepwise overview of the pathophysiology and management of acquired long QT syndrome in cirrhosis. The QT interval is mainly determined by ventricular repolarization. To compare the QT interval in time it should be corrected for heart rate (QTc), preferably by the Fridericia method. A QTc interval >450 ms in males and >470 ms in females is considered prolonged. The pathophysiological mechanism remains incompletely understood, but may include metabolic, autonomic or hormonal imbalances, cirrhotic heart failure and/or genetic predisposition. Additional external risk factors for QTc prolongation include medication (IKr blockade and altered cytochrome P450 activity), bradycardia, electrolyte abnormalities, underlying cardiomyopathy and acute illness. In patients with cirrhosis, multiple hits and cardiac-hepatic interactions are often required to sufficiently erode the repolarization reserve before long QT syndrome and TdP can occur. While some risk factors are unavoidable, overall risk can be mitigated by electrocardiogram monitoring and avoiding drug interactions and electrolyte and acidbase disturbances. In cirrhotic patients with prolonged QTc interval, a joint effort by cardiologists and hepatologists may be useful and significantly improve the clinical course and outcome. [ABSTRACT FROM AUTHOR]