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Regulation of gut microbiome by ketogenic diet in neurodegenerative diseases: A molecular crosstalk.Frontiers in Aging Neuroscience 2022The gut taxonomical profile is one of the contributory factors in maintaining homeostasis within the central nervous system (CNS). Of late, the efficacy of diet as a...
The gut taxonomical profile is one of the contributory factors in maintaining homeostasis within the central nervous system (CNS). Of late, the efficacy of diet as a target of treatment, and how various dietary interventions may modulate gut microbiota differently have been an area of focus in research. The role of ketogenic diet (KD) in particular has been well-established in other diseases like intractable epilepsy due to its postulated effects on gut microbiome modulation, resulting in neuronal stability and prevention of epileptogenesis. Therefore, this systematic review aimed to critically evaluate the current available literature investigating the interplay between the three distinct entities: ketogenic diet, neurodegeneration, and gut microbiota, which may serve as a focus guide for future neurodegenerative diseases (ND) therapeutic research. A comprehensive literature search was performed on three databases; PubMed, Scopus, and Ovid Medline. A total of 12 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that the hopes of KD as a treatment modality for ND are being ventured into as these individuals are said to acquire gut dysbiosis, primarily through increased colonization of phyla and . Although positive effects including restoration of healthy gut microbes such as sp., improvement in cognitive functioning and decline in neuro-inflammatory markers were noted, this systematic review also depicted conflicting results such as decrease in alpha and beta species diversity as well as diminution of healthy gut commensals such as . In addition, positive neuromodulation were also observed, notably an increase in cerebral blood perfusion to ventromedial hippocampal region increased expression of eNOS and clearance of amyloid-beta proteins across the blood-brain-barrier expression of p-glycoprotein. Neuroprotective mechanisms of ketogenic diet also included downregulation of mTOR expression, to prevention acceleration of pathological diseases such as Alzheimer's. Thus due to this conflicting/contrasting results demonstrated by ketogenic diet, such as a decline in gut species richness, diminution in beneficial microbes and decline cognition unless delivered in an intermittent fasting pattern, further studies may still be required before prior recommendation of a ketogenic diet therapeutic regime in ND patients.
PubMed: 36313018
DOI: 10.3389/fnagi.2022.1015837 -
Pharmacotherapy Apr 2022Colchicine and statins are frequently co-prescribed for prevention and treatment of cardiovascular diseases, auto-inflammatory diseases, and gout. Both are substrates... (Review)
Review
Colchicine and statins are frequently co-prescribed for prevention and treatment of cardiovascular diseases, auto-inflammatory diseases, and gout. Both are substrates and inhibitors of the cytochrome P-450 (CYP) 3A4 isozyme and P-glycoprotein so that taken together, they represent a clinically significant interaction. Data suggest the interaction may be associated with potentially life-threatening myopathies and rhabdomyolysis. The purposes of this systematic review (SR) were to gather and appraise evidence surrounding the statin-colchicine drug interaction and discuss related risk-mitigation strategies. An electronic literature search was performed. Twenty-one articles met the protocol to be included in the qualitative analysis: 18 case reports/series, 2 retrospective observational cohort studies, and 1 retrospective case-control study. Thirty-eight patients developed an adverse drug event (ADE) receiving statin-colchicine combination therapy; 25 (66%) patients developed myopathy; 10 (26%) patients developed rhabdomyolysis, and three (8%) patients developed neuromyopathy. Over 70% of patients developed ADEs on simvastatin or atorvastatin, and 80% of studies reported moderate-to-high intensity statins. Colchicine dosing varied but ranged between 0.5 to 1.5 mg daily. Sixty-two percent of patients in the case reports/series had comorbid renal disease. Seven studies (33% of all included studies) reported patients taking concomitant interacting medications at the CYP3A4 and/or P-glycoprotein efflux pump. Seventeen studies (81% of all included studies) reported ADEs leading to hospitalization. A multivariate analysis from one case-control study identified risk factors prognosticating myopathy ADEs in patients taking statin-colchicine therapy: comorbid renal disease and/or cirrhosis, colchicine doses 1.2 mg daily or greater, and concomitant interacting medications. Clinicians must be cognizant that the statin-colchicine drug interaction may lead to patient harm and thus should employ risk-mitigation strategies for statin-associated muscle symptoms. Future studies are warranted to validate clinically relevant risk factors that are strongly associated with the complications owing to the statin-colchicine drug interaction.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Case-Control Studies; Colchicine; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscular Diseases; Retrospective Studies; Rhabdomyolysis
PubMed: 35175631
DOI: 10.1002/phar.2674 -
Polypharmacy in polymorbid pregnancies and the risk of congenital malformations-A systematic review.Basic & Clinical Pharmacology &... Mar 2022With an increased prevalence of concurrent morbidities during pregnancy, polypharmacy has become increasingly common in pregnant women. The risks associated with...
With an increased prevalence of concurrent morbidities during pregnancy, polypharmacy has become increasingly common in pregnant women. The risks associated with polypharmacy may exceed those of individual medication because of drug-drug interactions. This systematic review aims to evaluate the risk of congenital malformations in polymorbid pregnancies exposed to first-trimester polypharmacy. PubMed, Embase and Scopus were searched to identify original human studies with first- trimester polypharmacy due to polymorbidity as the exposure and congenital malformations as the outcome. After screening of 4034 identified records, seven studies fulfilled the inclusion criteria. Four of the seven studies reported an increased risk of congenital malformations compared with unexposed or monotherapy, odds ratios ranging from 1.1 to >10.0. Particularly, short-term anti-infective treatment combined with other drugs and P-glycoprotein substrates were associated with increased malformation risks. In conclusion, knowledge is limited on risks associated with first-trimester polypharmacy due to polymorbidity with the underlying evidence of low quantity and quality. Therefore, an increased focus on pharmacovigilance to enable safe drug use in early pregnancy is needed. Large-scale register-based studies and better knowledge of placental biology are needed to support the clinical management of polymorbid pregnancies that require polypharmacy.
Topics: Abnormalities, Drug-Induced; Female; Humans; Placenta; Polypharmacy; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First
PubMed: 34841667
DOI: 10.1111/bcpt.13695 -
Cardiovascular Drugs and Therapy Aug 2023Non-vitamin K antagonist oral anticoagulants (NOACs) are excreted by P-glycoprotein (P-gp) and some are metabolized by CYP450 enzymes such as CYP3A4. Although fewer drug... (Meta-Analysis)
Meta-Analysis Review
Non-vitamin K Antagonist Oral Anticoagulants (NOACs) Versus Warfarin in Patients with Atrial Fibrillation Using P-gp and/or CYP450-Interacting Drugs: a Systematic Review and Meta-analysis.
PURPOSE
Non-vitamin K antagonist oral anticoagulants (NOACs) are excreted by P-glycoprotein (P-gp) and some are metabolized by CYP450 enzymes such as CYP3A4. Although fewer drug interactions are present with NOACs, it is unclear whether NOACs should also be preferred over vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) using pharmacokinetically interacting drugs. Therefore, the benefit-risk profile of NOACs versus VKAs was investigated in AF patients treated with P-gp and/or CYP450-interacting drugs.
METHODS
Using PubMed and Embase, randomized controlled trials and observational studies on the effectiveness and safety of NOACs versus VKAs in AF patients using P-gp and/or CYP450-interacting drugs were included. A meta-analysis was performed, calculating relative risks (RR) and 95% confidence intervals (CI) with the Mantel-Haenszel method.
RESULTS
Twelve studies were included, investigating 10,793 NOAC and 10,096 VKA users treated with P-gp/CYP3A4 inhibitors, whereas no studies on P-gp and/or CYP450-inducing drugs were identified. Compared to VKAs, NOACs were associated with a borderline non-significantly lower stroke or systemic embolism (stroke/SE) risk (RR 0.85, 95%CI (0.72-1.01)), significantly lower intracranial bleeding (RR 0.47, 95%CI (0.34-0.65)) and all-cause mortality risks (RR 0.87, 95%CI (0.79-0.95), but significantly higher gastrointestinal bleeding risk (RR 1.74, 95%CI (1.06-2.86)). Among AF patients using amiodarone, NOACs were associated with significantly lower stroke/SE (RR 0.71, 95%CI (0.54-0.93)) and intracranial bleeding risks (RR 0.51, 95%CI (0.29-0.88)), but significantly higher gastrointestinal bleeding risk (RR 2.15, 95%CI (1.24-3.72)) than VKAs.
CONCLUSION
The benefit-risk profile of NOACs compared to VKAs was preserved in AF patients using P-gp/CYP3A4 inhibitors, including amiodarone.
Topics: Humans; Warfarin; Anticoagulants; Atrial Fibrillation; ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Cytochrome P-450 CYP3A Inhibitors; Stroke; Intracranial Hemorrhages; Gastrointestinal Hemorrhage; Embolism; Amiodarone
PubMed: 34637052
DOI: 10.1007/s10557-021-07279-8 -
Clinical Therapeutics Nov 2021To best promote drug tolerability and efficacy in the clinic, data from drug-drug interaction (DDI) evaluations and subsequent translation of the results to DDI...
PURPOSE
To best promote drug tolerability and efficacy in the clinic, data from drug-drug interaction (DDI) evaluations and subsequent translation of the results to DDI prevention and/or management strategies must be incorporated into the US Food and Drug Administration (FDA) product labeling in a consistent manner because differences in language might result in varied interpretations. This analysis aimed to assess the consistency in DDI labeling language in New Drug Applications (NDAs).
METHODS
NDAs of recently approved drugs (2012-2020) that increase the exposure of digoxin, midazolam, and S-warfarin, index substrates of P-glycoprotein, cytochrome P450 (CYP) 3A, and CYP2C9 activity, respectively, were fully reviewed. Noninhibitors were also evaluated to appreciate the extent of mechanistic extrapolation in case of negative index studies.
FINDINGS
After a systematic review of the DDI studies available in NDAs, FDA-approved labeling, and commonly used clinical tertiary resources, differences in DDI results presentation and resulting clinical recommendations were found, even for inhibitors that affect similarly the exposure of the same index substrate. Studies with negative results were often reported in the labels without providing mechanistic interpretation, thus limiting the possible extrapolation of this information to other known substrates.
IMPLICATIONS
The variability in language affects how the information was presented to clinicians in tertiary resources. Strategies that aim to improve the translation of mechanistic DDI index studies into consistent labeling recommendations are briefly discussed in this review.
Topics: Digoxin; Drug Interactions; Humans; Language; Midazolam; Pharmaceutical Preparations; Product Labeling; Warfarin
PubMed: 34579970
DOI: 10.1016/j.clinthera.2021.08.016 -
Clinical Pharmacokinetics Sep 2021Patients affected by poverty-related infectious diseases (PRDs) are disproportionally affected by malnutrition. To optimize treatment of patients affected by PRDs, we...
BACKGROUND
Patients affected by poverty-related infectious diseases (PRDs) are disproportionally affected by malnutrition. To optimize treatment of patients affected by PRDs, we aimed to assess the influence of malnutrition associated with PRDs on drug pharmacokinetics, by way of a systematic review.
METHODS
A systematic review was performed on the effects of malnourishment on the pharmacokinetics of drugs to treat PRDs, including HIV, tuberculosis, malaria, and neglected tropical diseases.
RESULTS
In 21/29 PRD drugs included in this review, pharmacokinetics were affected by malnutrition. Effects were heterogeneous, but trends were observed for specific classes of drugs and different types and degrees of malnutrition. Bioavailability of lumefantrine, sulfadoxine, pyrimethamine, lopinavir, and efavirenz was decreased in severely malnourished patients, but increased for the P-glycoprotein substrates abacavir, saquinavir, nevirapine, and ivermectin. Distribution volume was decreased for the lipophilic drugs isoniazid, chloroquine, and nevirapine, and the α1-acid glycoprotein-bound drugs quinine, rifabutin, and saquinavir. Distribution volume was increased for the hydrophilic drug streptomycin and the albumin-bound drugs rifampicin, lopinavir, and efavirenz. Drug elimination was decreased for isoniazid, chloroquine, quinine, zidovudine, saquinavir, and streptomycin, but increased for the albumin-bound drugs quinine, chloroquine, rifampicin, lopinavir, efavirenz, and ethambutol. Clinically relevant effects were mainly observed in severely malnourished and kwashiorkor patients.
CONCLUSIONS
Malnutrition-related effects on pharmacokinetics potentially affect treatment response, particularly for severe malnutrition or kwashiorkor. However, pharmacokinetic knowledge is lacking for specific populations, especially patients with neglected tropical diseases and severe malnutrition. To optimize treatment in these neglected subpopulations, adequate pharmacokinetic studies are needed, including severely malnourished or kwashiorkor patients.
Topics: HIV Infections; Humans; Malaria; Malnutrition; Nevirapine; Pharmaceutical Preparations; Poverty
PubMed: 34060020
DOI: 10.1007/s40262-021-01031-z -
Evidence-based Complementary and... 2021The L. leaf is gaining interest as a potential therapeutic agent for alleviating dengue- and non-dengue-associated thrombocytopaenia. In that regard, safety... (Review)
Review
INTRODUCTION
The L. leaf is gaining interest as a potential therapeutic agent for alleviating dengue- and non-dengue-associated thrombocytopaenia. In that regard, safety considerations are as important as efficacy potential. The safety evaluation of botanical products for human use is complicated by variable formulations, complex phytochemical composition, and extrinsic toxicants. This review aimed to systematically collate related safety clinical and preclinical data, as well as reports on herb-drug interactions of leaf consumption.
METHODS
A systematic search using predetermined keywords on electronic databases (MEDLINE, Cochrane Library Central, LILACS, and Web of Science) and grey literature was conducted. Relevant clinical and preclinical studies were identified, screened, and analysed to present an overall safety profile of leaf consumption.
RESULTS
A total of 41 articles were included (23 clinical, 5 ongoing trials, and 13 preclinical) for descriptive analysis on study characteristics, adverse reactions, toxicity findings, and herb-drug interactions, from which 13 randomised controlled and quasiexperimental trials were further assessed for risk of bias and reporting quality. Overall, leaf consumption (in the form of juice and standardised aqueous extract) was well tolerated by adult humans for short durations (
ported safe consumption of leaf standardised aqueous extract in children (aged 1-12 years). Minor gastrointestinal side effects were most commonly reported. There are concerns about hepatotoxicity and reproductive toxicity in long-term use, supported by animal studies. Unfavourable herb-drug interactions with metformin, glimepiride, digoxin, ciprofloxacin, and artemisinin were accounted. CONCLUSION
leaf consumption in adults is generally safe for short-term use though cautioned in pregnancy and people with liver impairment. It has potential herb-drug interactions with oral hypoglycaemic agents, p-glycoprotein substrates, and antibiotics with cation chelating properties.
PubMed: 34040647
DOI: 10.1155/2021/5511221 -
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 -
Thrombosis Research Oct 2020Direct oral anticoagulants (DOACs) have emerged as safe and effective alternatives to Vitamin-K antagonists for treatment and prevention of arterial and venous... (Review)
Review
BACKGROUND
Direct oral anticoagulants (DOACs) have emerged as safe and effective alternatives to Vitamin-K antagonists for treatment and prevention of arterial and venous thrombosis. Due to their novelty, pharmacokinetic DOAC drug-drug interactions (DDIs) that result in clinical adverse events have not been well-documented.
OBJECTIVE
This study aims to systematically review reported pharmacokinetic DDIs resulting in clinical adverse events through documented observational evidence to better inform clinicians in clinical practice.
METHODS
A comprehensive literature review of EMBASE, MEDLINE, and Ovid HealthStar was conducted through March 10th, 2020. Two independent reviewers screened and extracted data from eligible articles according to pre-established inclusion and exclusion criteria. Articles reporting bleeding or thrombotic outcomes in non-controlled (observational) settings resulting from suggested pharmacokinetic DOAC DDIs were included.
RESULTS
A total of 5567 citations were reviewed, of which 24 were included following data extraction. The majority were case reports (n = 21) documenting a single adverse event resulting from a suspected DOAC DDI, while the remaining papers were a case series (n = 1) and cohort studies (n = 2). The most commonly reported interacting drugs were amiodarone and ritonavir (bleeding), and phenobarbital, phenytoin, and carbamazepine (thrombosis). Bleeding events more often resulted from a combined mechanism (P-glycoprotein AND CYP3A4 inhibition), whereas thrombotic events resulted from either combined OR single P-glycoprotein/CYP3A4 induction.
CONCLUSION
Current literature evaluating the real-world risk of DOAC DDIs is limited to few case reports and retrospective observational analyses. Clinicians are encouraged to continue to report suspected drug interactions resulting in adverse events.
Topics: Administration, Oral; Anticoagulants; Drug Interactions; Hemorrhage; Humans; Observational Studies as Topic; Pharmaceutical Preparations; Retrospective Studies
PubMed: 33213849
DOI: 10.1016/j.thromres.2020.08.016 -
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