Formulation, Optimization and In-Vivo Characterization of Thermosensitive In-Situ Nasal Gel Loaded with Bacoside a for Treatment of Epilepsy.

The intranasal route has demonstrated superior systemic bioavailability due to its extensive surface area, the porous nature of the endothelial membrane, substantial blood flow, and circumvention of first-pass metabolism. In traditional medicinal practices, Bacopa monnieri, also known as Brahmi, is known for its benefits in enhancing cognitive functions and potential effects in epilepsy. This study aimed to develop and optimize a thermosensitive in-situ nasal gel for delivering Bacoside A, the principal active compound extracted from Bacopa monnieri. The formulation incorporated Poloxamer 407 as a thermogelling agent and HPMC K4M as the Mucoadhesive polymer. A 32-factorial design approach was employed for Optimization. Among the formulations. F7 exhibited the most efficient Ex-vivo permeation through the nasal mucosa, achieving 94.69 ± 2.54% permeation, and underwent a sol-gel transition at approximately 30.48 °C. The study's factorial design revealed that gelling temperature and mucoadhesive strength were critical factors influencing performance. The potential of in-situ nasal Gel (Optimized Batch-F7) for the treatment of epilepsy was demonstrated in an in-vivo investigation using a PTZ-induced convulsion model. This formulation decreased both the occurrence and intensity of seizures. The optimized formulation F7 showcases significant promise as an effective nasal delivery system for Bacoside A, offering enhanced bioavailability and potentially increased efficacy in epilepsy treatment.

Karanjin-loaded soya lecithin-based ethosomal nanogel for the therapeutic intervention of psoriasis: formulation development, factorial design based-optimization,in vitroandin vivoassessment.

This study aimed to develop and optimize karanjin-loaded ethosomal nanogel formulation and evaluate its efficacy in alleviating symptoms of psoriasis in an animal model induced by imiquimod. These karanjin-loaded ethosomal nanogel, were formulated to enhance drug penetration into the skin and its epidermal retention. Karanjin was taken to formulate ethosomes due to its potential ani-psoriatic activity. Ethosomes were formulated using the cold method using 32full factorial designs to optimize the formulation components. 9 batches were prepared using two independent variablesX1: concentration of ethanol andX2: concentration of phospholipid whereas vesicle size (Y1) and percentage entrapment efficiency (Y2) were selected as dependent variables. All the dependent variables were found to be statistically significant. The optimized ethosomal suspension (B3) exhibited a vesicle size of 334 ± 2.89 nm with an entrapment efficiency of 94.88 ± 1.24% and showed good stability. The morphology of vesicles appeared spherical with smooth surfaces through transmission electron microscopy analysis. X-ray diffraction analysis confirmed that the drug existed in an amorphous state within the ethosomal formulation. The optimized ethosome was incorporated into carbopol 934 to develop nanogel for easy application on the skin. The nanogel underwent characterization for various parameters including spreadability, viscosity, pH, extrudability, and percentage drug content. The ethosomal formulation remarkably enhanced the skin permeation of karanjin and increased epidermal retention of the drug in psoriatic skin compared to marketed preparation and pure drug. A skin retention study showed that ethosomal nanogel formulation has 48.33% epidermal retention in 6 h.In vivo,the anti-psoriatic activity of karanjin ethosomal nanogel demonstrated significant improvement in psoriasis, indicated by a gradual decrease in skin thickness and scaling as reflected in the Psoriasis Severity Index grading. Therefore, the prepared ethosomal nanogel is a potential vehicle for improved topical delivery of karanjin for better treatment of psoriasis.

Improving medication adherence among persons with cardiovascular disease through m-health and community health worker-led interventions in Kerala; protocol for a type II effectiveness-implementation research-(SHRADDHA-ENDIRA).

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality worldwide, and at present, India has the highest burden of acute coronary syndrome and ST-elevation myocardial infarction (MI). A key reason for poor outcomes is non-adherence to medication. METHODS: The intervention is a 2 × 2 factorial design trial applying two interventions individually and in combination with 1:1 allocation ratio: (i) ASHA-led medication adherence initiative comprising of home visits and (ii) m-health intervention using reminders and self-reporting of medication use. This design will lead to four potential experimental conditions: (i) ASHA-led intervention, (ii) m-health intervention, (iii) ASHA and m-health intervention combination, (iv) standard of care. The cluster randomized trial has been chosen as it randomizes communities instead of individuals, avoiding contamination between participants. Subcenters are a natural subset of the health system, and they will be considered as the cluster/unit. The factorial cluster randomized controlled trial (cRCT) will also incorporate a nested health economic evaluation to assess the cost-effectiveness and return on investment (ROI) of the interventions on medication adherence among patients with CVDs. The sample size has been calculated to be 393 individuals per arm with 4-5 subcenters in each arm. A process evaluation to understand the effect of the intervention in terms of acceptability, adoption (uptake), appropriateness, costs, feasibility, fidelity, penetration (integration of a practice within a specific setting), and sustainability will be done. DISCUSSION: The effect of different types of intervention alone and in combination will be assessed using a cluster randomized design involving 18 subcenter areas. The trial will explore local knowledge and perceptions and empower people by shifting the onus onto themselves for their medication adherence. The proposal is aligned to the WHO-NCD aims of improving the availability of the affordable basic technologies and essential medicines, training the health workforce and strengthening the capacity of at the primary care level, to address the control of NCDs. The proposal also helps expand the use of digital technologies to increase health service access and efficacy for NCD treatment and may help reduce cost of treatment. TRIAL REGISTRATION: The trial has been registered with the Clinical Trial Registry of India (CTRI), reference number CTRI/2023/10/059095.

Green micellar factorial design optimized first derivative synchronous spectrofluorimetric method for tripelennamine and diphenhydramine determination in pharmaceutical gel.

A green micellar synchronous spectrofluorimetric method was developed and validated for simultaneous determination of tripelennamine hydrochloride and diphenhydramine in bulk and combined pharmaceutical formulation. Synchronous fluorescence of tripelennamine hydrochloride and diphenhydramine was determined using Δλ = 60 nm. The first derivative of synchronous fluorescence was computed to resolve overlap in the synchronous fluorescence spectra. Tripelennamine hydrochloride was quantified at 375 nm, whereas diphenhydramine was quantified at 293 nm; each is the zero-crossing point of the other. As diphenhydramine exhibited weak native fluorescence, micelle enhancement upon incorporation of sodium dodecyl sulfate was considered. Two-level full factorial design was carried out to optimize experimental parameters. Optimum conditions involved using SDS (2% w/v) along with Teorell and Stenhagen buffer (pH 9). The method was found to be linear over the range 0.2-4.5 and 0.2-5 µg/mL for tripelennamine and diphenhydramine, respectively, with limits of detection 0.211 and 0.159 µg/mL. The method was successfully applied for simultaneous determination of tripelennamine hydrochloride and diphenhydramine in laboratory-prepared gel containing all possible excipients with mean percent recoveries ±SD 100.59 ± 0.79 and 98.99 ± 0.98 for tripelennamine hydrochloride and diphenhydramine, respectively. The proposed method was proved to be eco-friendly using different greenness assessment tools.

Bayesian Analysis of Multi-Factorial Experimental Designs Using SEM.

Latent repeated measures ANOVA (L-RM-ANOVA) has recently been proposed as an alternative to traditional repeated measures ANOVA. L-RM-ANOVA builds upon structural equation modeling and enables researchers to investigate interindividual differences in main/interaction effects, examine custom contrasts, incorporate a measurement model, and account for missing data. However, L-RM-ANOVA uses maximum likelihood and thus cannot incorporate prior information and can have poor statistical properties in small samples. We show how L-RM-ANOVA can be used with Bayesian estimation to resolve the aforementioned issues. We demonstrate how to place informative priors on model parameters that constitute main and interaction effects. We further show how to place weakly informative priors on standardized parameters which can be used when no prior information is available. We conclude that Bayesian estimation can lower Type 1 error and bias, and increase power and efficiency when priors are chosen adequately. We demonstrate the approach using a real empirical example and guide the readers through specification of the model. We argue that ANOVA tables and incomplete descriptive statistics are not sufficient information to specify informative priors, and we identify which parameter estimates should be reported in future research; thereby promoting cumulative research.

Use of Statistics in Plant Cell Tissue Culture.

Statistics and experimental design are important tools for plant cell and tissue culture researchers and should be used when planning and conducting experiments as well as during the analysis and interpretation of experimental results. The chapter provides basic concepts important to the statistical analysis of data obtained from plant tissue culture experiments and illustrates the application of common statistical procedures to analyze binomial, count, and continuous data for experiments with different treatment factors as well as identifying trends of dosage treatment factors.

Factorial invariance of the Wechsler Intelligence Scale for Children, Fifth Edition, across the UK, US and Australia & New Zealand.

OBJECTIVES: This study examined the factorial invariance of the factor structure of the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) across the UK, US and Australia & New Zealand (A&NZ). The factorial equivalence of cognitive assessments should be demonstrated before assuming cross-culture generalizability and interpretations of score comparisons. METHODS: Data were obtained from the UK, US and A&NZ normative standardizations of the WISC-V. The samples consisted of 415 UK, 2200 US and 528 A&NZ children, aged 6-16. Confirmatory factor analysis was applied separately in each sample to establish the baseline model. Next, tests of factorial invariance were undertaken using the recommended hierarchical approach, firstly across the UK and A&NZ samples and then across the UK and US samples. RESULTS: The five-factor first-order scoring model was found to be excellent fit across all three samples independently. Strict factorial invariance of the WISC-V was demonstrated firstly across the UK and A&NZ and secondly the UK and US nationally representative standardization samples. Comparison of latent means found small but significant differences in female children across the UK and A&NZ samples. CONCLUSIONS: Consistent with previous research, these results demonstrate the generality of the WISC-V factor structure across the UK, US and A&NZ. Furthermore, as the WISC-V factor structure aligns with the Cattell-Horn-Carroll (CHC) model of cognitive abilities, the results add further support to the cross-cultural generalizability of the CHC model. Small but significant differences in latent factor scores found across samples support the development and use of local normative data.

Stabilization of ß-D-galactosidase in solution containing chitosan-based membrane: Central composite rotatable design.

ß-D-galactosidase is a hydrolase enzyme capable of hydrolyzing lactose in milk-based foods. Its free form can be inactivated in solution during the production of low-dosage lactose foods. Then, it is important to study strategies for avoiding the free enzyme inactivation with the aim of circumventing this problem. The stabilization of ß-D-galactosidase in aqueous solution after interactions with chitosan/eucalyptus sawdust composite membrane proved to be a potential strategy when optimized by central composite rotatable (CCR) design. In this case, the best experimental conditions for ß-D-galactosidase partitioning and stability in an aqueous medium containing the chitosan-based composite membrane reinforced with eucalyptus sawdust were i) enzyme/buffer solution ratio of 0.0057, ii) pH 5.6, iii) membrane mass of 50 mg, and iv) temperature lower than 37 °C. Significance was found for the linear enzyme/buffer solution ratio, linear temperature, and quadratic pH (p < 0.05) in the interval between 0 and 60 min of study. In the interval between 60 and 120 min, there was significance (p < 0.12) for linear temperature, the temperature-enzyme/buffer solution ratio interaction and the interaction between linear pH and linear enzyme/buffer solution ratio. The Pareto charts and response surfaces clearly showed all the effects of the experimental variables on the stabilization of ß-D-galactosidase in solution after interactions with the chitosan composite membrane. In this case, industrial food reactors covered with chitosan/eucalyptus sawdust composite membrane could be a strategy for the hydrolysis of lactose during milk-producing processes.

Enhanced low-cost lipopeptide biosurfactant production by Bacillus velezensis from residual glycerin.

Biosurfactants (BSFs) are molecules produced by microorganisms from various carbon sources, with applications in bioremediation and petroleum recovery. However, the production cost limits large-scale applications. This study optimized BSFs production by Bacillus velezensis (strain MO13) using residual glycerin as a substrate. The spherical quadratic central composite design (CCD) model was used to standardize carbon source concentration (30 g/L), temperature (34 °C), pH (7.2), stirring (239 rpm), and aeration (0.775 vvm) in a 5-L bioreactor. Maximum BSFs production reached 1527.6 mg/L of surfactins and 176.88 mg/L of iturins, a threefold increase through optimization. Microbial development, substrate consumption, concentration of BSFs, and surface tension were also evaluated on the bioprocess dynamics. Mass spectrometry Q-TOF-MS identified five surfactin and two iturin isoforms produced by B. velezensis MO13. This study demonstrates significant progress on BSF production using industrial waste as a microbial substrate, surpassing reported concentrations in the literature.

Design of Optimized Solid Lipid Nanoparticles of Montelukast Sodium and Assessment of Oral Bioavailability in Experimental Model.

INTRODUCTION: The objective of the reported work was to develop Montelukast sodium (MS) solid lipid nanoparticles (MS-SLNs) to ameliorate its oral bio-absorption. Herein, the highpressure homogenization (HPH) principle was utilized for the fabrication of MS-SLNs. METHOD: The study encompasses a 23 full factorial statistical design approach where mean particle size (Y1) and percent entrapment efficiency (Y2) were screened as dependent variables while, the concentration of lipid (X1), surfactant (X2), and co-surfactant (X3) were screened as independent variables. The investigation of MS-SLNs by DSC and XRD studies unveiled the molecular dispersion of MS into the SLNs while TEM study showed the smooth surface of developed MSSLNs. The optimized MS-SLNs exhibited mean particle size (MPS) = 115.5 ± 1.27 nm, polydispersity index (PDI) = 0.256 ± 0.04, zeta potential (ζ) = -21.9 ± 0.32 mV and entrapment efficiency (EE) = 90.97 ± 1.12 %. The In vivo pharmacokinetic study performed in Albino Wistar rats revealed 2.87-fold increments in oral bioavailability. RESULTS: The accelerated stability studies of optimized formulation showed good physical and chemical stability. The shelf life estimated for the developed MS-SLN was found to be 22.38 months. CONCLUSION: At the outset, the developed MS-SLNs formulation showed a significant increment in oral bioavailability and also exhibited excellent stability in exaggerated storage conditions.

Microfluidic preparation and optimization of (Kollicoat ® IR-b-PCL) polymersome for co-delivery of Nisin-Curcumin in breast cancer application.

This work aimed to develop amphiphilic nanocarriers such as polymersome based diblock copolymer of Kollicoat ® IR -block-poly(ε-caprolactone) (Kollicoat ® IR-b-PCL) for potential co-delivery of Nisin (Ni) and Curcumin (CUR) for treatment of breast cancer. To generate multi-layered nanocarriers of uniform size and morphology, microfluidics was used as a new technology. In order to characterise and optimize polymersome, design of experiments (Design-Expert) software with three levels full factorial design (3-FFD) method was used. Finally, the optimized polymersome was produced with a spherical morphology, small particle size (dH < 200 nm), uniform size distribution (PDI < 0.2), and high drug loading efficiency (Ni 78 % and CUR 93 %). Furthermore, the maximum release of Ni and CUR was found to be roughly 60 % and 80 % in PBS, respectively. Cytotoxicity assays showed a slight cytotoxicity of Ni and CUR -loaded polymersome (N- Ni /CUR) towards normal cells while demonstrating inhibitory activity against cancer cells compared to the free drugs. Also, the apoptosis assays and cellular uptake confirmed the obtained results from cytotoxic analysis. In general, this study demonstrated a microfluidic approach for preparation and optimization of polymersome for co-delivery of two drugs into cancer cells.

Development of the Home Environmental Scale of Accessibility Instrument for Spain.

BACKGROUND: Universal accessibility is one of the most active lines of intervention for people with disabilities and older adults. This accessibility has become a topic of growing interest regarding home access and use. Therefore, the main objective of this study was to create and validate a home assessment tool: the HESA II. METHODS: The study was conducted in four phases: (1) agreement on variables by an expert panel; (2) development of 90 items according to the AOTA framework; (3) pilot test with n = 20; and (4) final study with 156 subjects where confirmatory factor analysis was performed. RESULTS: The tool consisted of 85 items divided into five subscales related to each of the main spaces of Spanish homes: living room; kitchen; bedroom; and bathroom. CONCLUSIONS: The tool demonstrates good psychometric properties of reliability. The HESA II assesses home accessibility based on limitations in activity and participation restriction of the evaluated person as per the International Classification of Functioning, Disability, and Health rather than on a diagnosis, making it applicable to a wide range of groups.

Risperidone-Loaded Nasal Thermosensitive Polymeric Micelles: Quality by Design-Based Formulation Study.

The current research aims to develop thermosensitive polymeric micelles loaded with risperidone for nasal administration, emphasizing the added benefits of their thermosensitive behavior under nasal conditions. An initial risk assessment facilitated the advanced development process, confirming that the key indicators of thermosensitivity were suitable for nasal application. The polymeric micelles exhibited an average size of 118.4 ± 3.1 nm at ambient temperature and a size of 20.47 ± 1.2 nm at 36.5 °C, in both cases in monodisperse distribution. Factors such as pH and viscosity did not significantly impact these parameters, demonstrating appropriate nasal applicability. The model formulations showed a rapid, burst-like drug release profile in vitro, accompanied by a quick and high permeation rate at nasal conditions. Overall, the Quality by Design-based risk assessment process led to the development of an advanced drug delivery system capable of administering risperidone through the nasal cavity.

Design and Rationale of the CLEAR SYNERGY (OASIS 9) Trial: A 2x2 Factorial Randomized Controlled Trial of Colchicine versus placebo and Spironolactone versus placebo in Patients with Myocardial Infarction.

BACKGROUND: Patients experiencing myocardial infarction (MI) remain at high risk of future major adverse cardiovascular events (MACE). While low-dose colchicine and spironolactone have been shown to decrease post-MI MACE, more data are required to confirm their safety and efficacy in an unselected post-MI population. Therefore, we initiated the CLEAR SYNERGY (OASIS 9) trial to address these uncertainties. METHODS: The CLEAR SYNERGY trial is a 2 × 2 factorial randomized controlled trial of low-dose colchicine 0.5 mg daily versus placebo and spironolactone 25 mg daily versus placebo in 7,062 post-MI participants who were within 72 hours of the index percutaneous coronary intervention (PCI). We blinded participants, healthcare providers, research personnel, and outcome adjudicators to treatment allocation. The primary outcome for colchicine is the first occurrence of the composite of cardiovascular death, recurrent MI, stroke, or unplanned ischemia-driven revascularization. The co-primary outcomes for spironolactone are (1) the composite of the total numbers of cardiovascular death or new or worsening heart failure and (2) the first occurrence of the composite of cardiovascular death, new or worsening heart failure, recurrent MI or stroke. We finished recruitment with 7,062 participants from 104 centers in 14 countries on November 8, 2022, and plan to present the results in the fall of 2024. CONCLUSIONS: CLEAR SYNERGY is a large international randomized controlled trial that will inform the effects of low-dose colchicine and spironolactone in largely unselected post-MI patients who undergo PCI. (ClinicalTrials.gov Identifier: NCT03048825).

24 Factorial Design Formulation Optimization and In vitro Characterization of Desloratadine Nanosuspension Prepared Using Antisolvent Precipitation.

INTRODUCTION: Desloratadine, a second-generation antihistaminic drug, is poorly watersoluble and requires amelioration of the dissolution rate to improve its pharmacokinetics properties. METHOD: This study investigated the impact of polymer, surfactant types, and concentration on the particle size, zeta potential, and dissolution efficiency of nanosuspensions formulated through the solvent antisolvent precipitation method. To optimize the delivery of Desloratadine nanosuspension, we used Minitab software and a 4-factor, 2-level full factorial design. Physicochemical properties and drug release studies were conducted to evaluate the suggested nanosuspension formulations. The optimization goals included minimizing particle size and zeta potential while maximizing dissolution efficiencies. RESULT: The selected optimal nanosuspension demonstrated favourable values, including a particle size of 478.63 ± 15.67 nm, a zeta potential of -36.24 ± 3.21 mV, and dissolution efficiencies in double distilled water and buffer of 90.29 ± 3.75 % and 93.70 ± 3.67 %, respectively. The optimized formulation was subjected to additional analysis using X-ray powder diffraction (XPRD), scanning and transmission electron microscopy (SEM and TEM), and Fourier-transform infrared spectroscopy (FTIR). CONCLUSION: The optimized nanosuspension formulation also underwent further studies under optimal lyophilization conditions, revealing the effectiveness of mannitol as a cryoprotectant at a concentration of 8%.

Understanding Factorial Designs, Main Effects, and Interaction Effects: Simply Explained with a Worked Example.

A factorial design examines the effects of two independent variables on a single, continuous dependent variable. The statistical test employed to analyze the data is a two-way analysis of variance (ANOVA). This test yields three results: a main effect for each of the independent variables and an interaction effect between the two independent variables. This article explains factorial designs and two-way ANOVA with the help of a worked example using hypothetical data in a spreadsheet provided as a supplementary file. The main effects and interaction effects are explained and illustrated using tables and figures. A short discussion provides general notes about the concepts explained in this article, along with brief notes on repeated measures ANOVA and higher order ANOVAs. Many additional examples, with figures and explanations, are provided in the supplementary materials, which the reader is strongly encouraged to view.

Optimizing the physical activity intervention for older adults with mild cognitive impairment: a factorial randomized trial.

Background: Physical activity (PA) intervention is one of the most effective interventions to promote cognitive function of older adults with mild cognitive impairment (MCI). However, the level of PA remains low. Based on the two core interventions (X-CircuiT and health education), this study aimed to examine the effect of three implementation strategies (viz., role modeling, goal-setting, and reminding) on the PA level among older adults with MCI using the multiphase optimization strategy (MOST). Methods: Participants were randomized into one of eight conditions in a factorial design involving three factors with two levels: (i) role modeling (on vs. off); (ii) goal-setting (on vs. off); and (iii) reminding (on vs. off). The primary outcome was PA level at 12 weeks. The secondary outcomes were cognitive function, self-efficacy, and cost-effectiveness at 12 weeks. The intention-to-treat (ITT) analysis was performed as the main analysis and the per-protocol (PP) analysis as the sensitivity analysis. Results: A total of 107 participants were included and randomly assigned into three groups, each receiving different implementation strategies. The results of the multivariate regression analysis showed that the three implementation strategies, namely, reminding (B = 0.31, p < 0.01), role modeling (B = 0.21, p < 0.01), and goal-setting (B = 0.19, p < 0.01), could significantly improve PA level. Specifically, it was found that role modeling (B = 0.68, p = 0.03) could significantly improve cognitive function. There were no significant interactions among the three implementation strategies. Role modeling was the most cost-effective strategy, costing 93.41 RMB for one unit of PA. Conclusions: Role modeling was likely to be the best implementation strategy. The value-based and cost-effective PA intervention package could include the core intervention (X-CircuiT and health education) and implementation strategy (role modeling). Clinical Trial Registration: https://www.chictr.org.cn, The study was retrospectively registered on 30 June 2022 (ChiCTR2200061693).

Optimization of Biodiesel Production Process Using MoO3 Catalysts and Residual Oil: A Comprehensive Experimental 23 Study.

The study aimed to utilize MoO3 catalysts, produced on a pilot scale via combustion reaction, to produce biodiesel from residual oil. Optimization of the process was conducted using a 23 experimental design. Structural characterization of the catalysts was performed through X-ray diffraction, fluorescence, Raman spectroscopy, and particle size distribution analyses. At the same time, thermal properties were examined via thermogravimetry and differential thermal analysis. Catalytic performance was assessed following process optimization. α-MoO3 exhibited a monophasic structure with orthorhombic phase, whereas α/h-MoO3 showed a biphasic structure. α-MoO3 had a larger crystallite size and higher crystallinity, with thermal stability observed up to certain temperatures. X-ray fluorescence confirmed molybdenum oxide predominance in the catalysts, with traces of iron oxide. Particle size distribution analyses revealed polymodal distributions attributed to structural differences. Both catalysts demonstrated activity under all conditions tested, with ester conversions ranging from 93% to 99%. The single-phase catalyst had a long life cycle and was reusable for six biodiesel production cycles. The experimental design proved to be predictive and significant, with the type of catalyst being the most influential variable. Optimal conditions included α-MoO3 catalyst, oil/alcohol ratio of 1/15, and a reaction time of 60 min, resulting in high biodiesel conversion rates and showcasing the viability of MoO3 catalysts in residual oil biodiesel production.

Association of genetic variants related to combined lipid-lowering and antihypertensive therapies with risk of cardiovascular disease: 2 × 2 factorial Mendelian randomization analyses.

BACKGROUND: Lipid-lowering drugs and antihypertensive drugs are commonly combined for cardiovascular disease (CVD). However, the relationship of combined medications with CVD remains controversial. We aimed to explore the associations of genetically proxied medications of lipid-lowering and antihypertensive drugs, either alone or both, with risk of CVD, other clinical and safety outcomes. METHODS: We divided 423,821 individuals in the UK Biobank into 4 groups via median genetic scores for targets of lipid-lowering drugs and antihypertensive drugs: lower low-density lipoprotein cholesterol (LDL-C) mediated by targets of statins or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lower systolic blood pressure (SBP) mediated by targets of ß-blockers (BBs) or calcium channel blockers (CCBs), combined genetically lower LDL-C and SBP, and reference (genetically both higher LDL-C and SBP). Associations with risk of CVD and other clinical outcomes were explored among each group in factorial Mendelian randomization. RESULTS: Independent and additive effects were observed between genetically proxied medications of lipid-lowering and antihypertensive drugs with CVD (including coronary artery disease, stroke, and peripheral artery diseases) and other clinical outcomes (ischemic stroke, hemorrhagic stroke, heart failure, diabetes mellitus, chronic kidney disease, and dementia) (P > 0.05 for interaction in all outcomes). Take the effect of PCSK9 inhibitors and BBs on CVD for instance: compared with the reference, PCSK9 group had a 4% lower risk of CVD (odds ratio [OR], 0.96; 95%CI, 0.94-0.99), and a 3% lower risk was observed in BBs group (OR, 0.97; 95%CI, 0.94-0.99), while combined both were associated with a 6% additively lower risk (OR, 0.94; 95%CI, 0.92-0.97; P = 0.87 for interaction). CONCLUSIONS: Genetically proxied medications of combined lipid-lowering and antihypertensive drugs have an independent and additive effects on CVD, other clinical and safety outcomes, with implications for CVD clinical practice, subsequent trials as well as drug development of polypills.