Deaths from polydrugs involving four or more substances have increased dramatically in recent years.12 To combat high prices, Doctors in Washington State last year experimented with a cheaper blend containing three drugs: phenobarbital, chloral hydrate and morphine sulfate. The components are widely used and cost about $500 for a lethal dose. But the combination turned out to be too harsh, said Dr. Robert Wood, a volunteer medical advisor for End of Life Washington. We assume that two drugs are more likely to be combined if they share a large number of common drugs in the drug cocktail network. For example, if two drugs d1 and d2 have m in common with the respective partners n1 and n2 of the drug cocktail network, there will be three groups in the vicinity of the two drugs, that is, (1) m drugs, which are the neighbors of drugs d1 and d2; (2) n1 – m partners who are only the neighbors of the drug D1; and (3) the n2-m partners are the neighbors of the drug D2 only [45]. Suppose there are completely N drugs in the drug combination network, then a p-value between d1 and d2 can be calculated using the following equation: star drugs and their neighbors. (A) The distribution of pairs of drugs adjacent to blockbuster drugs. Neighboring pairs of blockbuster drugs can be divided into two groups depending on whether they have similar ATC codes or are used as effective combinations. (B) Schematic representation of the relationship between two neighbors d1 and d2 of a stellar drug.
(C) The percentage of effective combinations in adjacent drug pairs, where the TS is equal to or greater than a given threshold. The blue and red lines represent the network of medicine cocktails, respectively. the average of 1000 randomly generated combined networks. In addition, we looked at the proteins targeted by the 13 pivotal drugs in the drug cocktail network that contain target information. By mapping all proteins targeted by drugs from the drug-cocktail network to the human protein-protein interaction network extracted from the STRING database [30], we found that pivotal drugs tend to have a closer relationship with their combined partners in terms of the shortest distance between target proteins than drugs with similar ATC codes (see Figure 5A).5A). In addition, we analyzed the cellular locations of these target proteins of the 13 Hub drugs (see Figure 5B).5B). More than 70% of the target proteins of Hub drugs are membrane proteins, which is reasonable given that membrane proteins are widely used in various biological processes and represent the largest class of drug targets. In this study, we extracted 239 combinations of known effective drugs in pairs of DCDBs [21]. ATC code information for each drug was obtained from DrugBank [22]. Based on these datasets, we built a network of drug cocktails with 215 nodes and 239 edges (see Figure 11 for visualizing this network), where the nodes represent the drugs and an edge is connected when two drugs are found in an effective drug combination. Building this network can thus give readers a visual impression of the relationships between drugs that can form effective combinations. In addition, network theory can be used to explore possible combinatorial mechanisms between drugs.
In Figure 1.1, the size of each node approaches its degree, and the width of each edge approximates the therapeutic similarity (TS) (as defined in equation 3) between the two drugs connected by the edge, while the gray edges indicate that the two drugs connected by the edge have completely different therapeutic effects. In addition, we found 102 drugs that have at least two neighbors in the drug cocktail network, which we have hereinafter referred to as “featured drugs,” and 91 of them have target protein annotations in DrugBank. Wood and his colleagues developed a new option this summer, a mixture of four drugs containing diazepam, digoxin, morphine and propranolol, known as DDMP. It costs between $300 and $600. where ATCk(d) denotes all ATC codes at the k-th level of drug d. Note that a drug has five levels of ATC codes. A score, TS, is used to define the therapeutic similarity between two drugs: Part of the problem is that there are no specific numbers on mixed synthetic drugs, although this happens almost worldwide. In addition, many countries lack the capacity or resources to test drugs for data collection. The combination of drugs is the combination of different active ingredients that, compared to their individual components, can achieve better effectiveness with fewer side effects. Recently, it has become a popular and promising strategy for the discovery of new drugs, especially for the treatment of complex diseases, such as cancer [1-3]. Moduretic, for example, is the combination of amiloride and hydrochlorothiazide, a combination approved for the treatment of patients with hypertension [4,5]. Chan et al.
have identified a combination drug, Tri-Luma, to combat melasma (dark patches of the skin) of the face based on efficacy and safety experiments [6]. Agrawal et al. found two effective combinatorial regimens for the treatment of Huntington`s disease based on prior screening for Drosophila [7]. In addition, synergistic antiangiogenic effects have shown that a very low-dose combinatorial application of vinblastine (LAV) and rapamycin (RAP) inhibits endothelial cell proliferation in vitro and in vivo much more effectively than a single drug treatment [8]. Recently, Lehar et al. It has been found that synergistic drug combinations may have fewer side effects because synergistic drug combinations are generally more selective for certain cellular settings than individual agents, and the dosage of each compound in combination is comparatively reduced [9]. Despite considerable efforts over the past few decades to discover new drug combinations, the majority of effective combination drugs used in the clinic have been discovered through an experiment that typically requires laborious and time-consuming brute force screening of all possible combinations among approved individual drugs [10]. In a combination of drugs, one drug may promote or suppress the effect of another. For example, cyclosporine increases the effect of sirolimus, while bupropion decreases the effect of cyclosporine. As a result, two drugs may have a completely new effect that differs from that of individual drugs [11,12].
Therefore, the presence of potential drug interactions (RDIs) and the possibility of pharmacokinetic interventions between drugs could hinder the identification of effective drug combinations [13]. In addition, the number of possible combinations will increase exponentially with the increasing availability of individual drugs. For example, with four drugs, there will be six possible combinations. That number would be huge, given that there are thousands of approved drugs. Due to the huge space for researching possible combinations between known drugs, identifying optimal and effective drug combinations is a non-trivial and difficult task. The use of benzodiazepines to support the reducing effects of stimulants (such as amphetamines or ecstasy) can lead to dependence on both types of drugs.