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Journal of Ethnopharmacology Mar 2021Bisbenzylisoquinoline (BBIQ) alkaloids are generally present in plants of Berberidaceae, Monimiaceae and Ranunculaceae families in tropical and subtropical regions. Some...
RELEVANCE
Bisbenzylisoquinoline (BBIQ) alkaloids are generally present in plants of Berberidaceae, Monimiaceae and Ranunculaceae families in tropical and subtropical regions. Some species of these families are used in traditional Chinese medicine, with the effects of clearing away heat and detoxification, promoting dampness and defecation, and eliminating sores and swelling. This article offers essential data focusing on 13 representative BBIQ compounds, which are mainly extracted from five plants. The respective botany, traditional uses, phytochemistry, pharmacokinetics, and toxicity are summarized comprehensively. In addition, the ADME prediction of the 13 BBIQ alkaloids is compared and analyzed with the data obtained.
MATERIALS AND METHODS
We have conducted a systematic review of the botanical characteristics, traditional uses, phytochemistry, pharmacokinetics and toxicity of BBIQ alkaloids based on literatures collected from PubMed, Web of Science and Elsevier during 1999-2020. ACD/Percepta software was utilized to predict the pharmacokinetic parameters of BBIQ alkaloids and their affinity with enzymes and transporters.
RESULTS
Botany, traditional uses, phytochemistry, pharmacokinetic and toxicity of 13 alkaloids, namely, tetrandrine, dauricine, curine, trilobine, isotrilobine, cepharanthine, daurisoline, thalicarpine, thalidasine, isotetrandrine, liensinine, neferine and isoliensinine, have been summarized in this paper. It can't be denied that these alkaloids are important material basis of pharmacological effects of family Menispermaceae and others, and for traditional and local uses which has been basically reproduced in the current studies. The 13 BBIQ alkaloids in this paper showed strong affinity and inhibitory effect on P-glycoprotein (P-gp), with poor oral absorption and potent binding ability with plasma protein. BBIQ alkaloids represented by tetrandrine play a key role in regulating P-gp or reversing multidrug resistance (MDR) in a variety of tumors. The irrationality of their usage could pose a risk of poisoning in vivo, including renal and liver toxicity, which are related to the formation of quinone methide during metabolism.
CONCLUSION
Although there is no further clinical evaluation of BBIQ alkaloids as MDR reversal agents, their effects on P-gp should not be ignored. Considering their diverse distribution, pharmacokinetic characteristics and toxicity reported during clinical therapy, the quality standards in different plant species and the drug dosage remain unresolved problems.
Topics: Alkaloids; Animals; Benzylisoquinolines; Drugs, Chinese Herbal; Ethnobotany; Ethnopharmacology; Humans; Medicine, Chinese Traditional; Phytochemicals; Plants, Medicinal
PubMed: 33166629
DOI: 10.1016/j.jep.2020.113566 -
Journal of Interventional Cardiac... Jan 2019Amiodarone is a potent inhibitor of the CYP450:3A4 and inhibitor of the P-glycoprotein, both of which metabolize new oral anticoagulants (NOACs). Patients who are on... (Comparative Study)
Comparative Study
PURPOSE
Amiodarone is a potent inhibitor of the CYP450:3A4 and inhibitor of the P-glycoprotein, both of which metabolize new oral anticoagulants (NOACs). Patients who are on NOACs and are concomitantly treated with amiodarone may have a higher risk of major bleeding according to recent retrospective trials. Whether this increased risk outweighs the benefits of NOACs compared to warfarin is unknown. We aimed to compare clinical outcomes between NOACs and warfarin in patients with atrial fibrillation (AF) being treated with amiodarone.
METHODS
We performed a systematic review of MEDLINE, Cochrane, and Embase for randomized controlled trials that compared NOACs to warfarin for prophylaxis of ischemic stroke/thromboembolic events (TEs) in patients with AF and reported outcomes on TE, major bleeding, and intracranial bleeding (ICB). Risk ratio (RR) and 95% confidence intervals were measured using the Mantel-Haenszel method. Fixed effects model was used, and if heterogeneity (I2) was > 25%, effects were analyzed using a random model.
RESULTS
A total of four studies comparing NOACs to warfarin were included in the analysis. The total number of patients on amiodarone was 6197. Mean follow up was 23 ± 5 months. No statistically significant difference for TE prevention (RR, 0.73; 95% CI 0.50-1.07), major bleeding (RR, 1.02; 95% CI 0.68-1.53), or ICB outcomes (RR, 0.58; 95% CI 0.22-1.51) between patients on NOACs + amiodarone when compared to patients on warfarin + amiodarone.
CONCLUSION
Among patients with AF taking amiodarone, there is no increased risk of stroke, major bleeding, or ICB with NOACs compared to warfarin.
Topics: Administration, Oral; Aged; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Female; Humans; Male; Middle Aged; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Stroke; Survival Rate; Thromboembolism; Treatment Outcome; Warfarin
PubMed: 30128801
DOI: 10.1007/s10840-018-0427-y -
Pharmaceutical Research Sep 2020The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in apixaban...
PURPOSE
The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in apixaban disposition based on in vitro studies. Recommendations against co-administration of apixaban with inhibitors of these efflux transporters can be found throughout the literature as well as in the apixaban FDA label. However, the clinical relevance of such findings is questionable due to the high permeability and high solubility characteristics of apixaban.
METHODS
Using recently published methodologies to discern metabolic- from transporter- mediated drug-drug interactions, a critical evaluation of all published apixaban drug-drug interaction studies was conducted to investigate the purported clinical significance of efflux transporters in apixaban disposition.
RESULTS
Rational examination of these clinical studies using basic pharmacokinetic theory does not support the clinical significance of intestinal efflux transporters in apixaban disposition. Further, there is little evidence that efflux transporters are clinically significant determinants of systemic clearance.
CONCLUSIONS
Inhibition or induction of intestinal CYP3A4 can account for exposure changes of apixaban in all clinically significant drug-drug interactions, and lack of intestinal CYP3A4 inhibition can explain all studies with no exposure changes, regardless of the potential for these perpetrators to inhibit intestinal or systemic efflux transporters.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Biological Transport; Cytochrome P-450 CYP3A; Drug Interactions; Humans; Intestinal Absorption; Neoplasm Proteins; Pyrazoles; Pyridones
PubMed: 32996065
DOI: 10.1007/s11095-020-02927-4 -
Cells Mar 2024Chemoresistance is a challenge in cancer treatment, limiting the effectiveness of chemotherapy. Mushroom extracts have shown potential as treatments for cancer... (Review)
Review
Chemoresistance is a challenge in cancer treatment, limiting the effectiveness of chemotherapy. Mushroom extracts have shown potential as treatments for cancer therapies, offering a possible solution to overcome chemoresistance. This systematic review aimed to explore the role of mushroom extracts in enhancing chemotherapy and reversing chemoresistance in cancer cells. We searched the PubMed, Web of Science and Scopus databases, following the PRISMA guidelines, and registered on PROSPERO. The extracts acted by inhibiting the proliferation of cancer cells, as well as enhancing the effect of chemotherapy. The mechanisms by which they acted included regulating anti-apoptotic proteins, inhibiting the JAK2/STAT3 pathway, inhibiting the ERK1/2 pathway, modulating microRNAs and regulating p-glycoprotein. These results highlight the potential of mushroom extracts to modulate multiple mechanisms in order to improve the efficacy of chemotherapy. This work sheds light on the use of mushroom extracts as an aid to chemotherapy to combat chemoresistance. Although studies are limited, the diversity of mushrooms and their bioactive compounds show promising results for innovative strategies to treat cancer more effectively. It is crucial to carry out further studies to better understand the therapeutic potential of mushroom extracts to improve the efficacy of chemotherapy in cancer cells.
Topics: Agaricales; Neoplasms; MicroRNAs; MAP Kinase Signaling System
PubMed: 38534354
DOI: 10.3390/cells13060510 -
Pharmaceutical Research May 2021The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in...
PURPOSE
The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in rivaroxaban disposition based on in vitro studies, similar to what had previously been proposed for apixaban. We recently showed that these efflux transporters were not clinically relevant for apixaban disposition and examine here their relevance for this second Factor Xa inhibitor.
METHODS
Using recently published methodologies to discern metabolic- from transporter- mediated drug interactions, a critical evaluation was undertaken of 9 rivaroxaban studies reporting 12 DDIs, one study of food effects and one study of hepatic function.
RESULTS
Rationale examination of these clinical studies using basic pharmacokinetic theory finds little support for the clinical significance of intestinal efflux transporters in rivaroxaban disposition. Drug-drug interactions are most likely adequately predicted based on the level of CYP 3A metabolism.
CONCLUSION
These analyses indicate that inhibition of efflux transporters appears to have negligible, clinically insignificant effects on the rivaroxaban absorption process, which is consistent with the concern that predictions based on in vitro measures may not translate to a clinically relevant interaction in vivo. We emphasize the need to evaluate gastric emptying, dissolution and other processes related to absorption when using MAT changes to indicate efflux transporter inhibition.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Administration, Oral; Drug Interactions; Drug Liberation; Factor Xa Inhibitors; Gastric Emptying; Gastrointestinal Absorption; Humans; Intestinal Mucosa; Neoplasm Proteins; Pyrazoles; Pyridones; Rivaroxaban; Tissue Distribution
PubMed: 33847849
DOI: 10.1007/s11095-021-03039-3 -
Current Cancer Drug Targets 2020Breast cancer is the most probable cancer among women. However, the available treatment is based on targeting different stages of breast cancer viz., radiation therapy,...
PURPOSE
Breast cancer is the most probable cancer among women. However, the available treatment is based on targeting different stages of breast cancer viz., radiation therapy, hormonal therapy, chemotherapy, and surgical interventions, which have some limitations. The available chemotherapeutics are associated with problems like low solubility, low permeability, high first-pass metabolism, and P-glycoprotein efflux. Hence, the aforementioned restrictions lead to ineffective treatment. Multiple chemotherapeutics can also cause resistance in tumors. So, the purpose is to develop an effective therapeutic regimen for the treatment of breast cancer by applying a nanomedicinal approach.
METHODS
This review has been conducted on a systematic search strategy, based on relevant literature available on Pub Med, MedlinePlus, Google Scholar, and Sciencedirect up to November 2019 using keywords present in abstract and title of the review. As per our inclusion and exclusion criteria, 226 articles were screened. Among 226, a total of 40 articles were selected for this review.
RESULTS
The significant findings with the currently available treatment is that the drug, besides its distribution to the target-specific site, also distributes to healthy cells, which results in severe side effects. Moreover, the drug is less bioavailable at the site of action; therefore, to overcome this, a high dose is required, which again causes side effects and lower the benefits. Nanomedicinal approaches give an alternative approach to avoid the associated problems of available chemotherapeutics treatment of breast cancer.
CONCLUSION
The nanomedicinal strategies are useful over the conventional treatment of breast cancer and deliver a target-specific drug-using different novel drug delivery approaches.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Drug Delivery Systems; Female; Humans; Nanostructures; Theranostic Nanomedicine
PubMed: 32228423
DOI: 10.2174/1568009620666200331124113 -
Hamostaseologie Dec 2020Recombinant interleukin-2 (rIL-2) is indicated for metastatic renal cell carcinoma and melanoma. Over recent years low-dose rIL-2 has been studied for the treatment of...
Recombinant interleukin-2 (rIL-2) is indicated for metastatic renal cell carcinoma and melanoma. Over recent years low-dose rIL-2 has been studied for the treatment of autoimmune diseases and acute coronary syndrome because of its ability to expand and activate T regulatory (T) cells. However, several medical conditions potentially benefiting from rIL-2 administrations are characterized by an intrinsic prothrombotic risk, thus requiring concurrent anticoagulation. In our systematic review of the literature, we investigated the potential for drug interactions between oral anticoagulants and rIL-2 by assessing the influence of rIL-2 administration on transporters and cytochromes determining the pharmacokinetics of (direct) oral anticoagulants. We extracted data from 12 studies, consisting of 11 animal studies and one study in humans. Eight studies investigated the pharmacokinetics of P-glycoprotein (P-gp) substrates and reported that the intraperitoneal rIL-2 administration may inhibit intestinal P-gp. Four studies on hepatic cytochrome P450 yielded conflicting results. The only human study included in this systematic review concluded that rIL-2 suppresses the hepatic cytochrome P450, but only if given at higher doses. Based on the results from animal studies, the co-administration of rIL-2 and dabigatran etexilate, a substrate of intestinal P-gp, may lead to higher dabigatran plasma concentrations and bioavailability. Human studies should confirm whether this potential interaction is clinically relevant.
Topics: Animals; Drug Interactions; Factor Xa Inhibitors; Humans; In Vivo Dosimetry; Interleukin-2
PubMed: 32325520
DOI: 10.1055/a-1120-4064 -
Clinical Drug Investigation Nov 2020Direct oral anticoagulants (DOACs), as substrates of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein, are susceptible to drug-drug interactions (DDIs). Hepatitis C...
BACKGROUND
Direct oral anticoagulants (DOACs), as substrates of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein, are susceptible to drug-drug interactions (DDIs). Hepatitis C direct-acting antiviral agents (DAAs), via P-glycoprotein or CYP3A4 inhibition, may increase DOAC exposure with relevant bleeding risk. We performed a systematic review on DDIs between DOACs and DAAs.
METHODS
Two reviewers independently identified studies through electronic databases, until 7 July 2020, supplementing the search by reviewing conference abstracts and the ClinicalTrials.gov website.
RESULTS
Of 1386 identified references, four articles were finally included after applying the exclusion criteria. Three phase I clinical studies in healthy volunteers assessed interactions between dabigatran and glecaprevir/pibrentasvir, odalasvir/simeprevir, or sofosbuvir/velpatasvir/voxilaprevir, showing an increase in the dabigatran area under the concentration-time curve (AUC) by 138%, 103%, and 161%, respectively.
CONCLUSIONS
DOACs and DAAs are under-investigated for DDI risk. Real-world studies are needed to assess the clinical relevance of the pharmacokinetic interactions with dabigatran and describe the actual spectrum of possible DDIs between DAAs and other DOACs.
Topics: Anticoagulants; Antiviral Agents; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Hepatitis C; Humans
PubMed: 32809123
DOI: 10.1007/s40261-020-00962-y -
International Journal of Nanomedicine 2019The poor pharmacokinetic characteristics of most anticancer drugs have limited their clinical effectiveness. The application of nanoparticles as a novel drug delivery...
The poor pharmacokinetic characteristics of most anticancer drugs have limited their clinical effectiveness. The application of nanoparticles as a novel drug delivery system has provided opportunities to tackle the current challenges facing conventional drug delivery systems such as poor pharmacokinetics, lack of specificity to tumor cells, multidrug resistance, and toxicity. This systematic review aims to examine the application of pharmacokinetic studies of nanoparticles loaded in conventional drugs and herb-derived compounds for cancer therapy. The pharmacokinetic parameters of several herbal medicines and chemotherapeutic drugs loaded into nanoparticles were reported. This included area under the curve (AUC) of plasma concentration-time profile, maximum plasma concentration (C), time to maximum plasma concentration (T), volume of distribution (V or V), elimination half-life (t), and clearance (CL). The systematic review was conducted using information available in the PubMed and Science Direct databases up to February 2019. The search terms employed were: pharmacokinetics, pharmacokinetic study, nanoparticles, anticancer, traditional medicine, herbal medicine, herb-derived compounds, natural products, and chemotherapy. Overall, nanoparticle carriers not only significantly improved pharmacokinetics but also further enhanced permeability, solubility, stability, specificity, and selectivity of the carried anticancer drugs/herb-derived compounds to target tumor cells. Additionally, they also limited hepatic first-pass metabolism and P-glycoprotein (P-gp) efflux of the carried anticancer drugs/herb-derived compounds. Based on this systematic review, polymeric nanoparticles were the most commonly used nanocarrier to improve the pharmacokinetic parameters. The use of nanoparticles as a novel drug delivery system has the potential to improve both pharmacokinetics and cytotoxicity activity of the loaded drugs/herb-derived compounds for cancer therapy.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Humans; Nanoparticles; Neoplasms; Plants, Medicinal
PubMed: 31632004
DOI: 10.2147/IJN.S213229 -
BMC Complementary Medicine and Therapies Jun 2020African Potato (hypoxis hemerocallidea), is used for enhancing immune system in Southern Africa. It is among the plants of intense commercial and scientific interest;...
BACKGROUND
African Potato (hypoxis hemerocallidea), is used for enhancing immune system in Southern Africa. It is among the plants of intense commercial and scientific interest; hence, the aim of this study was to describe its chemistry and pharmacology.
METHODS
PubMed, Cochrane Controlled Trials Register (CENTRAL) and Google Scholar were searched independently for relevant literature. The last search occurred in October 2018. Other research material was obtained from Google. The following search terms were used, but not limited to: "African Potato", "hypoxis", "hemerocallidea", "rooperol." Articles that were explaining the chemistry and pharmacology of hypoxis hemerocallidea were included.
RESULTS
Thirty articles from PubMed, Cochrane and Google Scholar were eligible. Three webpages were included from Google. Results showed that the tuberous rootstock (corm) of African Potato is used traditionally to treat wasting diseases, testicular tumours, insanity, barrenness, impotency, bad dreams, intestinal parasites, urinary infection, cardiac disease and enhancing immunity. The plant contains hypoxoside, which is converted rapidly to a potent antioxidant, rooperol in the gut. The corm contains sterols, sterol glycosides, stanols, terpenoids, saponins, cardiac glycosides, tannins and reducing sugars. A dose of 15 mg/kg/day of hypoxoside is reportedly therapeutic. Preclinical studies of African Potato have shown immunomodulation, antioxidant, antinociceptive, hypoglycaemic, anti-inflammatory, anticonvulsant, antibacterial, uterolytic, antimotility, spasmolytic and anticholinergic effects. The common side effects of African Potato are nausea and vomiting, which subside over time. In vitro, African Potato demonstrated inhibitory effects on CYP1A2, 2C9, 2D6, 3A4, 3A5, CYP19-metabolism and induction of P-glycoprotein. In vivo, it did not alter the pharmacokinetics of efavirenz or lopinavir/ritonavir.
CONCLUSION
African Potato is mainly used as an immunostimulant. The exact mechanisms of action for all the pharmacological actions are unknown. More research is required to substantiate claims regarding beneficial effects. There are many research gaps that require investigation including pharmacokinetic interactions with conventional drugs, especially those used in HIV/AIDS.
Topics: Africa; Catechols; Humans; Hypoxis; Medicine, African Traditional; Plant Extracts; Plants, Medicinal
PubMed: 32527245
DOI: 10.1186/s12906-020-02956-x