Drug Strategy Research Articles

Alcohol consumption, heavy episodic drinking and the perpetration of antisocial behaviours in Australia

AimsThis study aims to understand the dose-response relationship of the volume and patterns of alcohol consumption with alcohol-related antisocial behaviours (ASB) in the general population and assess whether these relationships are consistent across various sociodemographic subgroups. MethodsWe used data from 30,275 respondents aged (14−69) from two waves (2013 and 2016) of the National Drug Strategy Household Survey (NDSHS). Average daily alcohol consumption and heavy episodic drinking (HED) frequencies were treated as the main independent variables and self-reported ASB perpetration as the dependent variable. Bivariable and multivariable logistic regression models predicting ASB with interaction terms between alcohol consumption and various sociodemographic variables were estimated. FindingsCompared with low-risk drinking (0.01–20 g of alcohol/day), respondents drinking at risky (20.01–40 g of alcohol/day) and high risk (>40 g of alcohol per day) levels had an increased prevalence of ASB perpetration with adjusted odds ratios of 3.63 (95% CI 2.98–4.42) and 8.07 (6.72–9.71). Increasing frequency of HED was also linked to increased self-report of ASB perpetration in bivariable and multivariable models. In our interaction models, we found higher probabilities of ASB perpetration among younger and unmarried respondents for a given level of drinking. Discussion and conclusionsBoth average daily alcohol consumption and frequency of HED predict the probability of perpetrating alcohol-related ASB. Unsurprisingly, the risk of alcohol-specific ASB increased more quickly with consumption levels for younger and single respondents, suggesting interventions to reduce consumption among younger and unmarried persons will significantly impact ASB.

A New Strategy for Multitarget Drug Discovery/Repositioning Through the Identification of Similar 3D Amino Acid Patterns Among Proteins Structures: The Case of Tafluprost and its Effects on Cardiac Ion Channels.

The identification of similar three-dimensional (3D) amino acid patterns among different proteins might be helpful to explain the polypharmacological profile of many currently used drugs. Also, it would be a reasonable first step for the design of novel multitarget compounds. Most of the current computational tools employed for this aim are limited to the comparisons among known binding sites, and do not consider several additional important 3D patterns such as allosteric sites or other conserved motifs. In the present work, we introduce Geomfinder2.0, which is a new and improved version of our previously described algorithm for the deep exploration and discovery of similar and druggable 3D patterns. As compared with the original version, substantial improvements that have been incorporated to our software allow: (i) to compare quaternary structures, (ii) to deal with a list of pairs of structures, (iii) to know how druggable is the zone where similar 3D patterns are detected and (iv) to significantly reduce the execution time. Thus, the new algorithm achieves up to 353x speedup as compared to the previous sequential version, allowing the exploration of a significant number of quaternary structures in a reasonable time. In order to illustrate the potential of the updated Geomfinder version, we show a case of use in which similar 3D patterns were detected in the cardiac ions channels NaV1.5 and TASK-1. These channels are quite different in terms of structure, sequence and function and both have been regarded as important targets for drugs aimed at treating atrial fibrillation. Finally, we describe the in vitro effects of tafluprost (a drug currently used to treat glaucoma, which was identified as a novel putative ligand of NaV1.5 and TASK-1) upon both ion channels’ activity and discuss its possible repositioning as a novel antiarrhythmic drug.

Simulation Models for Prediction of Bioavailability of Medicinal Drugs-the Interface Between Experiment and Computation.

The oral drug bioavailability (BA) problems have remained inevitable over the years, impairing drug efficacy and indirectly leading to eventual human morbidity and mortality. However, some conventional lab-based methods improve drug absorption leading to enhanced BA, and the recent experimental techniques are up-and-coming. Nevertheless, some have inherent drawbacks in improving the efficacy of poorly insoluble and low impermeable drugs. Drug BA and strategies to overcome these challenges were briefly highlighted. This review has significantly unravelled the different computational models for studying and predicting drug bioavailability. Several computational approaches provide mechanistic insights into the oral drug delivery system simulation of descriptors like solubility, permeability, transport protein-ligand interactions, and molecular structures. The in silico techniques have long been known still are just being applied to unravel drug bioavailability issues. Many publications have reported novel applications of the computational models towards achieving improved drug BA, including predicting gastrointestinal tract (GIT) drug absorption properties and passive intestinal membrane permeability, thus maximizing time and resources. Also, the classical molecular simulation models for free solvation energies of soluble-related processes such as solubilization, dissolutions, supersaturation, and precipitation have been used in virtual screening studies. A few of the tools are GastroPlusTM that supports biowaiver for drugs, mainly BCS class III and predicts drug compounds' absorption and pharmacokinetic process; SimCyp® simulator for mechanistic modelling and simulation of drug formulation processes; pharmacodynamics analysis on non-linear mixed-effects modelling; and mathematical models, predicting absorption potential/maximum absorption dose. This review provides in silico-experiment annexation in the drug bioavailability enhancement, possible insights that lead to critical opinion on the applications and reliability of the various in silico models as a growing tool for drug development and discovery, thus accelerating drug development processes.

Ionic Liquids for Enhanced Drug Delivery: Recent Progress and Prevailing Challenges.

Ionic liquids (ILs) are a class of nonmolecular compounds composed only of ions. Compared with traditional organic solvents, ILs have the advantages of wide chemical space, diverse and flexible structures, negligible vapor pressure, and high thermal stability, which make them widely used in many fields of modern science, such as chemical synthesis and catalytic decomposition, electrochemistry, biomass conversion, and biotransformation biotechnology. Because of their special characteristics, ILs have been favored in the pharmaceutical field recently, especially for the development of efficient drug delivery systems. So far, ILs have been successfully designed to promote the dissolution of poorly soluble drugs and the destruction of physiological barriers, such as the tight junction between the stratum corneum and the intestinal epithelium. In addition, ILs can also be combined with other drug strategies to stabilize the structure of small molecules. This Review mainly introduces the application of ILs in drug delivery, emphasizes the potential mechanism of ILs, and presents the key research directions of ILs in the future.

An international comparative analysis of public reimbursement of orphan drugs in Canadian provinces compared to European countries

BackgroundThe Canadian government has committed to developing a national strategy for drugs for rare diseases starting in 2022. Considering this announcement, we conducted a comparative analysis to examine patient access to therapies for rare disease in Canada relative to Europe and the U.S.MethodsGiven its similarity to the Canadian health care system, we used Europe as the reference point to analyze all of the therapies with an orphan drug designation approved by the European Medicine Agency (EMA) from 1 January 2015 to 31 March 2020. We then contrasted access to these drugs in Canada (Health Canada) and the U.S. (Food and Drug Administration, FDA). We focused on: (1) the number of therapies for rare diseases entering the Canadian market; (2) the percentage of these therapies that are publicly available to Canadians; and (3) the timelines for patients to access these therapies in Canada.ResultsSixty-three approved therapies with an orphan drug designation from the EMA were identified. Fifty-three (84%) of these drugs had also been submitted to the FDA for approval, and 41 (65%) were submitted to Health Canada for approval. In Europe, Germany, Denmark, and the U.K. had the highest percentage of publicly reimbursed orphan drugs (84%, 70%, 68%, respectively). In comparison, Ontario (32%), Quebec (25%), and Alberta (25%) had the highest percentage of drugs reimbursed among the Canadian provinces. The shortest median duration (in months) from EMA approval to jurisdictional decision on reimbursement was in Austria (3.2), followed by Germany (4.1), and Finland (6.0). In Canada, the shortest median duration (in months) from regulatory approval to reimbursement was in British Columbia (17.3), Quebec (19.6) and Manitoba (19.6), while the longest duration was in P.E.I (38.5), followed by Nova Scotia (25.9), and Newfoundland (25.1).ConclusionsOur comparative analysis found that relative to the EU Canadians had less frequent and timely access to therapies for rare diseases. This highlights the need for a rare disease strategy in Canada that allows for clear identification and transparent tracking of the pathway for rare disease drugs, and ultimately optimizes the number of patients with access to these therapies.

Overdose prevention centres in the UK

Overdose prevention centres in the UK

Sauna-like conditions or menthol treatment reduce tau phosphorylation through mild hyperthermia

In Alzheimer's disease (AD), hyper-phosphorylation and aggregation of tau correlate with clinical progression and represent a valid therapeutic target. A recent 20-year prospective study revealed an association between moderate to high frequency of Finnish sauna bathing and a lower incidence of dementia and AD, but the molecular mechanisms underlying these benefits remain uncertain. Here, we tested the hypothesis that sauna-like conditions could lower tau phosphorylation by increasing body temperature. We observed a decrease in tau phosphorylation in wild-type and hTau mice as well as in neuron-like cells when exposed to higher temperatures. These effects were correlated with specific changes in phosphatase and kinase activities, but not with inflammatory or heat shock responses. We also used a drug strategy to promote thermogenesis: topical application of menthol, which led to a sustained increase in body temperature in hTau mice, concomitant with a significant decrease in tau phosphorylation. Our results suggest that sauna-like conditions or menthol treatment could lower tau pathology through mild hyperthermia, and may provide promising therapeutic strategies for AD and other tauopathies.

Impact of ErbB Receptors and Anticancer Drugs against Breast Cancer: A Review.

Human EGFR (epidermal growth factor receptor) family of tyrosine kinase receptors consists of four members, ErbB1-4. Abnormalities in the ErbB family characterize a variety of human cancers, including breast cancer. Tyrosine kinase is recruited by the activated EGFR cell surface receptor, which transmitted signals from the receptor to interact with intracellular signaling pathways and regulate cellular functions and biological processes. Targeting the intracellular signaling pathways has been aided in the drug development that was already in use and more continually being developed. The review article highlights the function of ErbB receptors/ligands, their role in signaling pathways, effective targeted drugs, and a combination of targeted drug strategies in the treatment of breast cancer that could be leading to the novel combination of anticancer drug delivery systems.

A survey of optimal strategy for signature-based drug repositioning and an application to liver cancer.

Pharmacologic perturbation projects, such as Connectivity Map (CMap) and Library of Integrated Network-based Cellular Signatures (LINCS), have produced many perturbed expression data, providing enormous opportunities for computational therapeutic discovery. However, there is no consensus on which methodologies and parameters are the most optimal to conduct such analysis. Aiming to fill this gap, new benchmarking standards were developed to quantitatively evaluate drug retrieval performance. Investigations of potential factors influencing drug retrieval were conducted based on these standards. As a result, we determined an optimal approach for LINCS data-based therapeutic discovery. With this approach, homoharringtonine (HHT) was identified to be a candidate agent with potential therapeutic and preventive effects on liver cancer. The antitumor and antifibrotic activity of HHT was validated experimentally using subcutaneous xenograft tumor model and carbon tetrachloride (CCL4)-induced liver fibrosis model, demonstrating the reliability of the prediction results. In summary, our findings will not only impact the future applications of LINCS data but also offer new opportunities for therapeutic intervention of liver cancer.

Pleiotropic Effects of Simvastatin and Losartan in Preclinical Models of Post-Traumatic Elbow Contracture.

Elbow trauma can lead to post-traumatic joint contracture (PTJC), which is characterized by loss of motion associated with capsule/ligament fibrosis and cartilage damage. Unfortunately, current therapies are often unsuccessful or cause complications. This study aimed to determine the effects of prophylactically administered simvastatin (SV) and losartan (LS) in two preclinical models of elbow PTJC: an in vivo elbow-specific rat injury model and an in vitro collagen gel contraction assay. The in vivo elbow rat (n = 3–10/group) injury model evaluated the effects of orally administered SV and LS at two dosing strategies [i.e., low dose/high frequency/short duration (D1) vs. high dose/low frequency/long duration (D2)] on post-mortem elbow range of motion (via biomechanical testing) as well as capsule fibrosis and cartilage damage (via histopathology). The in vitro gel contraction assay coupled with live/dead staining (n = 3–19/group) evaluated the effects of SV and LS at various concentrations (i.e., 1, 10, 100 µM) and durations (i.e., continuous, short, or delayed) on the contractibility and viability of fibroblasts/myofibroblasts [i.e., NIH3T3 fibroblasts with endogenous transforming growth factor-beta 1 (TGFβ1)]. In vivo, no drug strategy prevented elbow contracture biomechanically. Histologically, only SV-D2 modestly reduced capsule fibrosis but maintained elevated cellularity and tissue hypertrophy, and both SV strategies lessened cartilage damage. SV modest benefits were localized to the anterior region, not the posterior, of the joint. Neither LS strategy had meaningful benefits in capsule nor cartilage. In vitro, irrespective of the presence of TGFβ1, SV (≥10 μM) prevented gel contraction partly by decreasing cell viability (100 μM). In contrast, LS did not prevent gel contraction or affect cell viability. This study demonstrates that SV, but not LS, might be suitable prophylactic drug therapy in two preclinical models of elbow PTJC. Results provide initial insight to guide future preclinical studies aimed at preventing or mitigating elbow PTJC.

A VA Federal Supply Schedule (VAFSS)–based cost-effectiveness analysis of immunotherapy-tyrosine kinase inhibitor (IO-TKI) regimens and sunitinib in the treatment of metastatic renal cell carcinoma (mRCC).

312 Background: Recent FDA approvals for mRCC treatment have resulted in increased effectiveness, drug choices, and costs. We performed a cost effectiveness analysis (CEA) of six recently approved IO-TKI drug combinations and sunitinib. Methods: We used a Markov simulation model from the healthcare sector perspective with a lifetime time horizon. The 7 treatment drug strategies considered in this model included: (1) atezolizumab + bevacizumab (AB), (2) avelumab + axitinib (AA), (3) pembrolizumab + axitinib (PA), (4) nibolumab + ipilimumab(NI), (5) nibolumab + cabozantinib (NC), (6) lenvatinib + pembrolizumab (LP), and (7) sunitinib (S). Input parameters of drug effectiveness and toxicities to construct the model were based on published randomized studies that led to drug approvals. Direct costs for treatment were derived using the VA Federal Supply Schedule (VAFSS). Markov model simulates patient transition between 3 health states at monthly intervals: progression free, progressive disease, and death. The cost-effectiveness outcome in our model were and life-years (LYs), progression-free life-years (PFLYs) gained, and quality-adjusted life-years (QALYs) with utility values based on published literature. Results: The table highlights results of the CEA. The least expensive drug combination was NI ($442,218) while the most expensive was LP ($963,610). AA yielded the most LYs (5.51) and QALYs (5.62) and LP yielded the most PFLYs (1.64) while NL yielded the least LYs (4.35) and PFLYs (1.47) and LP yielded the least QALYs (4.19). AB and S were absolutely dominated strategies yielding less effectiveness and cost more in terms of effectiveness measures. Depending on acceptable willingness-to-pay (WTP) and effectiveness measures, PA or AA were the most cost-effective strategies. Conclusions: Our analyses suggest that based on direct cost acquisition using VA FSS, PA or AA were cost-effective strategies for mRCC with WTP of $20,000 to $200,000 per QALY.[Table: see text]

In Vitro Antibacterial Experiments of Qixingjian Decoction and Its Synergistic Interaction with Oxacillin against Clinical Isolates of Methicillin-Resistant Staphylococcus aureus.

Background With the widespread use and abuse of antimicrobial drugs, the problem of bacterial resistance is becoming increasingly prominent. The clinical detection rate of drug-resistant bacteria is increasing year by year, so there is an urgent need to develop new antimicrobial drugs. Qixingjian Decoction (QXJT) is a formula commonly used in Chinese medicine for the treatment of sepsis caused by acute purulent infections of the face, hands, and feet. There are many compounds with antimicrobial effects that are available, but little is known about their mode of action. In this study, we mainly evaluated the antimicrobial activity of QXJT and explored its synergistic interaction with oxacillin (OX) and the mechanism of its antimicrobial activity. Methods The antimicrobial activity of QXJT against methicillin-resistant Staphylococcus aureus (MRSA) was determined by the microdilution method, the broth macrodilution method, and the time-kill curve method. The main compounds in QXJT were analyzed by ultra-performance liquid chromatography. The synergistic interaction of QXJT and oxacillin (OX) was determined by checkerboard assay, and the antimicrobial mechanism of QXJT, OX, and QXJT + OX was evaluated by transmission electron microscopy (TEM) technique. The expression of MRSA superantigen virulence factors (sea, seb, and tst), and drug resistance gene (mecA) was detected to provide a new strategy for new antibiotic drugs. Results QXJT exhibited antimicrobial activity against both clinical isolates of MRSA, MICs ranging from 18.75 to 37.5 mg/mL. Active substances such as Scutellarein, Scutellarin, Apigenin, and Wogonin 7-O-glucuronide were detected in the phytochemical analysis that may be associated with the antimicrobial activity of QXJT. The synergistic effect of QXJT and OX was determined by checkerboard assay (FICI = 0.5), and TEM images showed that QXJT could cause the disruption of MRSA cell wall, and QXJT + OX could produce greater disruption of MRSA cell wall, elucidating the synergistic effect of the two together on cell wall disruption by microscopic mechanisms. Our study shows that the combination of QXJT and OX can inhibit the expression of MRSA virulence factor, reduce the virulence of MRSA, and have no significant effect on the expression of MRSA resistance gene mecA. Conclusion The results of this study provide scientific experimental data for the traditional application of QXJT and initially explore the mechanism of action of QXJT combined with OX.

WITHDRAWN: Covid-19 Study, Pathology and Therapeutics

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Binding Studies of the Prodrug HAO472 to SARS-Cov-2 Nsp9 and Variants.

SARS-CoV-2 (COVID-19) has infected over 219 million people and caused the death of over 4.55 million worldwide. In a previous screen of a natural product library against purified SARS-CoV-2 Nsp9 using a native mass spectrometry-based approach, we identified an ent-kaurane natural product, oridonin (1), with micromolar affinities. In this work, we have found that the prodrug HAO472 (2) directly binds to Nsp9, establishing replacement of the labile ester with a bioisostere as a candidate drug strategy. We further tested 1 and its clinical analogue 2 against two Nsp9 variants from human coronavirus 229E (HCoV-229E) and ferret systemic coronavirus F56 (FSCoV-F56). Both compounds showed significant binding selectivity to COVID-19 and HCoV-229E Nsp9 over FSCoV-F56 Nsp9, confirming the covalent bond with Cys73.

Increasing cocaine use amongst employed Australians: who is most at-risk?

Australian's cocaine use is at record levels. Large increases occurred between 2016-2019, with significant increases predominately found among employed Australians. Patterns, and prevalence of workers' cocaine use were examined using the 2016 and 2019 National Drug Strategy Household Survey data via frequency analyses. Logistic regression modelling identified predictors of employed Australian's: cocaine use (2019); and increased use over time (2016-2019). Workers' cocaine use increased 63% between 2016-2019 (3.8%-6.2%). Predictors of use, and increased use, were age, marital status, state, remoteness, smoking status, alcohol use, and cocaine approval level. Income and psychological distress predicted cocaine use in 2019 only. Highest prevalence in 2019 occurred among workers who approved of regular cocaine use (47.9%), currently smoked (14.9%), were very highly distressed (14.0%), risky alcohol consumers (13.7%), and aged 18-24 years (13.9%). Numerous individual-level characteristics influence workers' cocaine use. Workplace cultural norms and substance use climates may facilitate increased cocaine use. The workplace is a powerful setting for cocaine prevention and intervention efforts. Potential strategies include targeting social norms, shifting positive drug use workplace cultures, and providing health and safety training focussing on the risk of use to self and co-workers whilst also examining demographic subgroups' motivations for use.

University students’ experiences of recreational class a drug taking and perspectives on personal, social and health education (PSHE) drug education

PurposeResearch suggests that student drug use is substantially higher than that of the general population and while the UK Government’s current Drug Strategy emphasises the importance of PSHE in preventing young people from becoming drug users, there is a lack of research investigating the longer-term effectiveness of drug prevention education, and students’ views using qualitative methods. The purpose of this paper is to gain a holistic understanding into university students’ lived experiences of recreational class A drug taking and the drug education taught in English secondary schools.Design/methodology/approachFive interviews with university students were undertaken and thematically analysed using an ideographic case study approach alongside a qualitative content analysis of publicly available drug education resources and policy documents.FindingsThe normalisation of drug taking at university and social micro-pressures to assimilate group norms were key contributing factors to participants’ drug use. While the content of drug education in PSHE is grounded in theory, its implementation is not.Originality/valueThis study extends upon existing theories of normalisation of drug use at university through the concept of micro-pressures to offer an explanation of the process by which students assimilate group norms through the implicit threat of not fitting in.

If cannabis use is increasing among workers what are the implications for policy? A secondary analysis of a nationally representative Australian dataset

Patterns, prevalence and predictors of past year cannabis use were examined by industry and occupation groups through secondary analyses of Australia’s triennial National Drug Strategy Household Surveys (2010, 2013, 2016, 2019). Frequency analyses examined cannabis prevalence. Logistic regression models estimated adjusted effects of demographics on cannabis use amongst employees overall, and within industries and occupations where prevalence differed from the employed national average. Workers’ cannabis use increased 17.4% between 2010 and 2019. Workers most likely to use cannabis in all models were male, smokers, aged 14–24 years, and with very high psychological distress levels. Prevalence was highest among trade workers (18.2%) and those in Arts and Recreation Services (26.6%). The greatest relative increases occurred in industries where prevalence levels were traditionally very low. To date, cannabis-related workplace policies and interventions have been predicated on any level of use being potentially risky. However, greater social acceptability, more lenient legal constraints, and increased medicinal use of cannabis necessitates approaches that reflect changing social norms and address the needs of workers vulnerable to harm. Findings highlight the importance of reconceptualizing risk mitigation strategies and implementing novel and effective prevention, intervention approaches and policies tailored to specific workforce settings and populations with differing risk profiles.

Management of epilepsy in Lebanon: Medication reviews and drug-related problems.

The goal of epilepsy treatment is to control seizures without drug related problems (DRPs). The evaluation of anti-seizure drugs (ASD) strategies and identification of DRPs are rarely studied. This study aimed primarily to evaluate the choice of ASD according to international guidelines and secondarily to identify and describe anti-seizure drug-related problems. A cross-sectional study was conducted during 1 year among Lebanese adults with epilepsy attending neurology clinics. The choice of ASD was compared to National Institute for Health and Care Excellence guidelines. Drug-drug interactions were evaluated by the Lexicomp database, and the DRP classification was performed using the Pharmaceutical Care Network Europe classification. A total of 404 patients with epilepsy were included. The prescription for an ASD was in accordance with the indication set in guidelines in 75.0% of population, and 1078 DRPs were identified. The main DRPs detected were adverse drug reactions (51.0%), inappropriate combinations of drugs (50.0%), and suboptimal drug regimens (46.3%). Single and divorced patients, who living in Mount Lebanon, and who took the old with the new generation had a less risk to have an inadequate prescription to guidelines. However, female gender, controlled epilepsy, multiple ASDs, and living in a rural region increased DRPs. This study showed that quarter of the population used ASDs contraindicated according to international guidelines. Since DRPs were related to the number and type of ASD prescribed, it is important to assess the case of each patient by a clinical pharmacist to prevent drug-drug interactions and iatrogenic issues.

Oral Administration of Bacterial β Cell Expansion Factor A (BefA) Alleviates Diabetes in Mice with Type 1 and Type 2 Diabetes.

Diabetes mellitus (DM) is a group of metabolic diseases, and there is an urgent need to develop new therapeutic DM oral drugs with fewer side effects and sound therapeutic efficacy. In this study, a β cell expansion factor A (BefA) production strain of Escherichia coli (BL21-pet 28C-BefA) was constructed, and the antidiabetes effect of BefA was evaluated using type 1 DM (T1DM) and type 2 DM (T2DM) mice models. The T1DM mice results indicated that BefA significantly reduced blood glucose levels; exerted a protective effect on islet β cell morphology; downregulated the expressions of TLR-4, p-NFκB/NFκB, and Bax/Bcl-2, and the secretion levels of IL-1β and TNF-α; increased the expression of PDX-1 protein and insulin secretion in a concentration-dependent manner; and restored the disturbed microbial diversity to normal levels. Similarly with the T1DM mice, BefA obviously increased islet β cells and reduced the inflammatory reaction and apoptosis in T2DM mice, as well as improved liver lipid metabolism by downregulating the expressions of CEBP-α, ACC, and Fasn; inhibited the synthesis of triglycerides; and induced Cpt-1, Hmgcs2, and Pparα in a concentration-dependent manner. In conclusion, BefA alleviates diabetes via increasing the number of islet β cells, reducing the inflammatory reaction and apoptosis, improving liver lipid metabolism, and restoring microbial diversity to normal levels, which provides a new strategy for a DM oral drug.

Research on government subsidy strategies for new drug R&D considering spillover effects

This paper studies the pharmaceutical production supply chain system composed of upstream and downstream pharmaceutical enterprises, and explores the impact of government subsidy strategies on the new drug research and development (R&D) decision variables and profits of pharmaceutical enterprises as well as social welfare, when considering both the horizontal spillover effects within the industry and the vertical spillover effects between industries. Comparing and analyzing the impact of these strategies including non-government subsidy strategy, pharmaceutical enterprise innovation input subsidy strategy, pharmaceutical enterprise innovative product subsidy strategy, patient price subsidy strategy, and patient medical insurance subsidy strategy. By establishing a four-stage Cournot duopoly model incorporating spillover effects, the equilibrium solutions are obtained by backward induction, and the impact of spillover effects on decision variables is investigated accordingly. Studies have shown that: (a) Government subsidy strategies can promote pharmaceutical enterprises’ R&D investment and have a positive incentive effect on the pharmaceutical enterprises’ profits and social welfare. (b) The patient medical insurance subsidy strategy is the optimal subsidy strategy, which can generate higher profits for pharmaceutical enterprises and higher social welfare. (c) The horizontal and vertical spillover effects have different effect on decision variables, enterprises’ profits and social welfare under various subsidy strategies.