The real problem with prescribing drugs that share the CYP3A4 pathway has been seen with drugs whose levels are not measured. When the serum levels of these drugs reach a toxic state, the toxicity can manifest itself with serious medical consequences. The pro-arrhythmic effects from high serum levels of the nonsedating antihistamines terfenadine and astemizole have severely limited their usefulness and led to the development of newer agents to take their place. Mibefradil (Posicor), a potent inhibitor of CYP3A4, was withdrawn from the market after numerous reports of serious drug-drug interactions.
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Adverse Drug Event Reporting reviews current sources of information on adverse drug events, including the FDA's MedWatch program and the AERS, institutional review boards, and the CMS. This report considers the ways that consumers and advocacy groups can be involved in reporting adverse events, and discusses drug interactions, problems with current databases for capturing and evaluating interactions, and difficulties in communicating information about adverse drug interactions. This report also describes new requirements for information contained on drug labels and how labels can be used to communicate information about risks and drug interactions to consumers and practitioners.
One of the tools that clinicians trust into review patients' medication sheet for DDIs is computerized DDI software. By manual review of drug regimens by pharmacists, without the use of utility (e.g., drug interaction reference and computer program), only 66% of DDIs in a 2-drug regimen can be correctly identified and the proportion decreases substantially as the number of drugs increases.[5] While a DDI screening program can be highly desirable, there is concern about variation between programs and about quality and effectiveness of the information. Thus, clinicians should be aware of the advantages and limitations of the DDI applications. In 2001, Hazlet et al. reported that up to 33% of relevant drug interactions were not recognized by computer software.[6] Another problem is the numerous alerts of insignificant drug interactions by software. Clinicians are likely to ignore excessive alerts of unimportant drug interactions, which may also lead to potential unfavorable consequences.[7]
Among the different computer platforms, the personal digital assistant (PDA) is frequently used for finding drug interactions. Like desktop interaction software, PDA drug interaction software often derives from familiar handbooks, textbooks, and internet sources that can be updated regularly. In addition, PDA software can be accessible at the point of patient care and because of the ease of use are expected to substitute for standard references. Only a few studies have compared some PDA drug interaction software programs such as iFacts, Micromedex, Lexi-Interact, Pharmavista, and Epocrates with each other, to select the best program regarding accuracy, comprehensiveness, and ease of use.[8,9]
On the one hand, we wanted to get more information about the interacting drug (highest comprehensiveness). On the other hand, the resource reliability is very important. Thus, it is important for DDI screening programs to contain a part that shows references related to each interaction monograph. Programs may cite evidence for interaction from a study without a control group to identify confounding factors. An interaction's evidence may also originate from hypothetical or study-based pharmacokinetic findings that do not contain outcomes assessment. Among five programs that we assessed, only two of them (Lexi-Interact and iFacts) included references to interaction evidence. There are, in addition, other deficiencies. Interaction monographs often do not include detectable patient and medication risk factors that make nonsevere drug interactions clinically important. Another problem about the reliability of the programs is a lack of standardization in assigning levels of significance to the interaction.[18,19] Among the five drug interaction software programs in this study, disagreement on the severity of interactions was seen. Other studies supported our results.[16,20] This discrepancy in severity rating of identified DDIs between electronic software programs can be explained with inconsistency of evidence and different criteria for the classification of severity of DDIs by various software.[16]
Many drug interactions are related to the dose of drugs that are consumed together. For example, some drugs may have interaction in high doses, but if they are used in lower doses, they will not lead to interaction. An ideal DDI screening program should be able to ignore an interaction if the drugs are given in doses that will not result in interaction.[18,21] Among the five programs that we evaluated, none of them had this ability. Other studies reported that the software programs also do not consider dosing of the drugs in the assessment of DDIs.[17,22] Therefore, one option should be defined in software programs, so clinicians can insert the dose of suspected drugs. Another limitation of 5 understudied drug interaction software programs is that they cannot detect the DDIs regarding duplicate prescription, for example, co-administration of two beta-blockers or two benzodiazepines. In this condition, it is expected that the software will identify the type of interaction as contraindicated. None of the mentioned software programs was able to detect such an interaction. Hence, improvement is needed to advance the DDI screening programs contribution to detection of DDIs.
Finally, our results support previous literature in this area. Studied have indicated variation and deficiencies in DDI screening programs. Of the five drug interaction screening programs evaluated, none was considered to be ideal. However, Lexi-Interact was better than others. Improvement is needed to advance the DDI screening programs contribution to detection of DDIs. A good suggestion is to check interaction pairs by more than one program, for example, two programs and compare their results to achieve more sensitivity. Moreover, as a final point, the clinician's judgment is so important to distinguish relevant from irrelevant interactions.
The use of multiple medicines, commonly referred to as polypharmacy is common in the older population with multimorbidity, as one or more medicines may be used to treat each condition. Polypharmacy is associated with adverse outcomes including mortality, falls, adverse drug reactions, increased length of stay in hospital and readmission to hospital soon after discharge [6,7,8]. The risk of adverse effects and harm increases with increasing numbers of medications [9]. Harm can result due to a multitude of factors including drug-drug interactions and drug-disease interactions. Older patients are at even greater risk of adverse effects due to decreased renal and hepatic function, lower lean body mass, reduced hearing, vision, cognition and mobility [10].
Of the 110 studies included in the review, only one highlighted the inconsistencies in the definitions of polypharmacy in the literature. The authors of this study suggested that polypharmacy be defined as patients visiting multiple pharmacies which may be associated with safety concerns relating to potential outcomes such as medication duplication, drug-drug interactions and adverse effects [112].
"Patients with more than 5 prescription medications have a higher risk for drug interactions, and many elderly patients have lists of 10 or even 20 medications to sift through, so any help with narrowing down the major drug interactions is helpful."
"I treat a large volume of HIV patients and ARV regimens are notorious for potential drug-drug interactions. A reputable and reliable drug-drug interaction software program has always been an essential part of my practice."
See Table 1 for clinically significant drug interactions, including contraindicated drugs. Drugs listed in Table 1 are a guide and not considered a comprehensive list of all possible drugs that may interact with PAXLOVID. Consider the potential for drug interactions prior to and during PAXLOVID therapy; review concomitant medications during PAXLOVID therapy and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7)].
Prediction of drug-target interactions (DTI) plays a vital role in drug development in various areas, such as virtual screening, drug repurposing and identification of potential drug side effects. Despite extensive efforts have been invested in perfecting DTI prediction, existing methods still suffer from the high sparsity of DTI datasets and the cold start problem. Here, we develop KGE_NFM, a unified framework for DTI prediction by combining knowledge graph (KG) and recommendation system. This framework firstly learns a low-dimensional representation for various entities in the KG, and then integrates the multimodal information via neural factorization machine (NFM). KGE_NFM is evaluated under three realistic scenarios, and achieves accurate and robust predictions on four benchmark datasets, especially in the scenario of the cold start for proteins. Our results indicate that KGE_NFM provides valuable insight to integrate KG and recommendation system-based techniques into a unified framework for novel DTI discovery.
a Betweenness centrality distribution of the network consisting of DTI data and all KG. Degree means the number of the edges linked to a node. The betweenness centrality of a node reflects the amount of the control that this node exerts over the interactions of the other nodes in the network. b The visualization of the KG related to the selected DTI (D00964 and has:1553), where the green points represent proteins, the blue points represent heterogeneous information and the red points represent drugs. c Betweenness centrality distribution of the network for the KG related to the selected DTI (D00964 and has:1553). d The visualization of the selected DTI (D00964 and has:1553) related knowledge graph with removing the nodes and related edges of KEGG_GENE, KEGG_Drug and KEGG_PATHWAY. e Betweenness centrality distribution of the network consisting of the selected DTI (D00964 and has:1553) related KG with removing the nodes and related edges of KEGG_GENE, KEGG_Drug and KEGG_PATHWAY. 2ff7e9595c
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