Application of pharmacoepidemiological approaches to generate real-world evidence on the use and impact of metastatic colorectal cancer medicines

Introduction: Metastatic colorectal cancer (mCRC) is characterised by multiple treatment strategies. Randomised clinical trials are not always aligned with clinical practice, and greater use of real-world (RW) studies has been suggested to inform health care decisions by providing results that reflect RW practice. Methods: This thesis utilised multiple methods. First, a systematic review and meta-analyses (SRMA) of RW studies including mCRC patients treated with first-line (1L) systemic anti-cancer therapy (SACT) was conducted to explore the comparative safety and effectiveness, including overall survival (OS), progression free survival (PFS) and objective response of 1L mCRC SACTs. Second, a retrospective observational cohort study using linkage of routinely collected data of mCRC patients treated with 1L SACT in NHS GGC from 01/01/2015 to 31/12/2016 was performed to investigate the factors influencing selection of 1L mCRC SACTs, treatment pathways, and treatment outcomes including median OS (mOS) and time-to-next-treatment (TTNT) of mCRC patients. Results: Between 2015 and 2016, A total of 220 new mCRC SACT users were identified in NHS GGC, with 52.3% (N=115) of the patients treated with a doublet of FOLFOX or FOLFIRI, 22.3% (N=49) with 5FU, 19.5% (N=43) with cetuximab+FOLFIRI, and 5% (N=11) of patients treated initially with aflibercept+FOLFIRI. Treatment choices for 1L mCRC were made based on patients’ age and gender, tumour RAS status, and previous treatment response. The median overall survival (mOS) for these patients was statistically influenced by the initial mCRC SACT and the performance status. The combination of cetuximab+FOLFIRI demonstrated a statistically significant prolonged mOS compared to 5FU (HR 0.4 (95% CI 0.24-0.85) and the longest time to next treatment (TTNT (12.93 months (95%CI 5.85-15.25)). The SRMA also indicated an OS, PFS, and overall response rate benefit for bevacizumab+chemotherapy over chemotherapy alone with a statistically increased risk of non-haematological toxicities and a non-statistically significant increased risk for haematological toxicity. Conclusions: Real-world evidence can help understand the impact of mCRC SACT on evidence-based practice.Introduction: Metastatic colorectal cancer (mCRC) is characterised by multiple treatment strategies. Randomised clinical trials are not always aligned with clinical practice, and greater use of real-world (RW) studies has been suggested to inform health care decisions by providing results that reflect RW practice. Methods: This thesis utilised multiple methods. First, a systematic review and meta-analyses (SRMA) of RW studies including mCRC patients treated with first-line (1L) systemic anti-cancer therapy (SACT) was conducted to explore the comparative safety and effectiveness, including overall survival (OS), progression free survival (PFS) and objective response of 1L mCRC SACTs. Second, a retrospective observational cohort study using linkage of routinely collected data of mCRC patients treated with 1L SACT in NHS GGC from 01/01/2015 to 31/12/2016 was performed to investigate the factors influencing selection of 1L mCRC SACTs, treatment pathways, and treatment outcomes including median OS (mOS) and time-to-next-treatment (TTNT) of mCRC patients. Results: Between 2015 and 2016, A total of 220 new mCRC SACT users were identified in NHS GGC, with 52.3% (N=115) of the patients treated with a doublet of FOLFOX or FOLFIRI, 22.3% (N=49) with 5FU, 19.5% (N=43) with cetuximab+FOLFIRI, and 5% (N=11) of patients treated initially with aflibercept+FOLFIRI. Treatment choices for 1L mCRC were made based on patients’ age and gender, tumour RAS status, and previous treatment response. The median overall survival (mOS) for these patients was statistically influenced by the initial mCRC SACT and the performance status. The combination of cetuximab+FOLFIRI demonstrated a statistically significant prolonged mOS compared to 5FU (HR 0.4 (95% CI 0.24-0.85) and the longest time to next treatment (TTNT (12.93 months (95%CI 5.85-15.25)). The SRMA also indicated an OS, PFS, and overall response rate benefit for bevacizumab+chemotherapy over chemotherapy alone with a statistically increased risk of non-haematological toxicities and a non-statistically significant increased risk for haematological toxicity. Conclusions: Real-world evidence can help understand the impact of mCRC SACT on evidence-based practice

Comparative effectiveness and safety of first-line systemic anti-cancer treatments of metastatic colorectal cancer : a systematic review and meta-analysis

Background: metastatic colorectal cancer (mCRC) is characterised by multiple treatment strategies. Randomised clinical trials are not always aligned with the clinical practice, and greater use of realworld (RW) studies has been suggested to inform health care decisions by providing results that reflect RW practice. The purpose of this systematic review and meta-analysis was to provide a synthesis of the available RW evidence on the effectiveness and safety of first-line systemic anti-cancer therapies (SACTs) in patients with mCRC. Methods: relevant databases were searched from inception until July 2021. Inclusion criteria were observational studies; published in English; patients ≥ 18 years; mCRC; first-line SACT for treatment of mCRC. No restrictions were placed on the country of publication. The effectiveness outcomes included overall survival (OS), the primary outcome, and progression-free survival (PFS). Safety was assessed by the occurrence of grade 3 or 4 adverse effects based on the national cancer institute common terminology criteria for adverse events (NCI CTCAE). The results were synthesised using a randomeffect meta-analysis model based on Hazard ratio and 95% confidence interval (95% CI) for survival outcomes, while risk ratio and 95% CI was used for safety outcome. Subgroup analysis was performed to explore differences between different treatment strategies. Heterogeneity was assessed using I2. Results: The search strategy identified 5662 studies, of which 31 met the inclusion criteria and were included in the overall survival meta-analysis. The pooled hazard ratio for overall survival, including all SACTs, was 1.19 (1.1-1.29). The overall heterogeneity of included studies was 76.6%. Subgroup analysis identified a significant difference between different treatment comparisons (p =0.01). The pooled overall survival was significant for chemotherapy only versus Bevacizumab+ chemotherapy (pooled estimate: 1.15 (1.05-1.26). For PFS, 20 studies were included in the meta-analysis. The pooled hazard ratio, including all SACTs, was 1.19 (1.08- 1.3), with an overall heterogeneity of the included studies was 64.4%. subgroup analysis showed a significant difference between different comparisons (p=0.001). the pooled PFS was significant for: (1) chemotherapy only versus bevacizumab+ chemotherapy (pooled estimate: 1.36 (1.05-1.26) and (2) bevacizumab+ irinotecan-based chemotherapy versus bevacizumab+ oxaliplatinbased chemotherapy (pooled estimate: 1.22 (1.07-1.38). For the safety outcomes, 14 studies were included in the meta-analysis. The pooled relative risk of haematological and non-haematological toxicities was 1.25 (0.89-1.76) and 1.03 (0.73-1.46), respectively, with no statistically significant difference between different treatment strategies for the haematological toxicities (p > 0.05). However, the pooled estimate for non-haematological toxicities was significant for two subgroups (1) bevacizumab+ XELIRI versus bevacizumab+ FOLFIRI (pooled estimate 1.66 (1.03-2.7). and bevacizumab+ FOLFOXIRI versus bevacizumab+ XELOXIRI (pooled estimate: 3.5 (1.9-6.4). Conclusion: The results indicated a survival benefit for bevacizumab with additional nonhaematological toxicities for several combinations involving bevacizumab used in first-line settings of mCRC treatment. Although the survival benefit may appear clinically modest, bevacizumab offers hope for increased survival for patients with mCRC

Describing systemic anti-cancer therapy pathways in metastatic colorectal cancer patients using real-world data

Background: The rapid uptake of new medicines for metastatic colorectal cancer (mCRC), together with the wide range of potential combinations and sequences available for treating mCRC, presents challenges for clinicians in deciding the optimal treatment plan for their patients. Published studies describing treatment pathways for mCRC in routine practice are scarce, mainly due to the complexity of the clinical pathways that depend on a combination of patients' characteristics, tumour clinicopathological characteristics, and previous treatment outcomes. This study aims to illustrate the variation in treatment pathways in mCRC patients in NHS Greater Glasgow and Clyde (NHS GGC). Methods: National and local Scottish datasets, including the chemotherapy electronic prescribing and administration system (CEPAS), the Scottish Cancer Registry, and the national records of Scotland, were linked retrospectively using the Scottish community health index (CHI) number as a common identifier. Data for adult patients diagnosed with mCRC and who received at least one mCRC systemic anti-cancer treatment (SACT) in NHS GGC from 01/01/2015 to 31/12/2016 were used to develop a Sankey plot in R studio to illustrate the treatment pathways. Patients were followed up until death, loss to follow up or end of the study on February 28, 2018, whichever occurred first. Results: A total of 277 patients were identified; 220 (79.4%) patients had no prior mCRC SACT before the study period. The initial SACT in the study for most patients was a doublet of either FOLFOX (n=60, 21.7%), CAPOX (n=26, 9.3%) or FOLFIRI (n=6, 22.4%), whilst 54 (18.8%) patients received 5-fluorouracil monotherapy, and 75 (26.1%) patients received triplet therapy of cetuximab + FOLFIRI or aflibercept + FOLFIRI. Overall, 39 unique SACT pathways were identified, as shown in figure 1. 209 (75.5%) patients received only one line of SACT, and 68 (24.5%) patients received at least two different lines of SACT during the study. Of these, 18 (26.5%) patients had their initial SACT downgraded from a triplet to a doublet or from a doublet to monotherapy, whereas 19 (27.9%) patients had their initial SACT upgraded from monotherapy to a doublet or from a doublet to triplet. Only six patients received three distinctive treatment lines during the study timeframe. The median duration for the first SACT treatment was 112 days (IQR: 57-167 days), whereas the median time from the first SACT to the second line of SACT was 222.5 days (IQR: 98-319 days). And the median time from the end of the first SACT and the beginning of the second SACT was 80 days (IQR: 21-163 days). Conclusion: Visualisation tools such as the Sankey plot can describe the complex treatment pathways in routine practice. Although Sankey plots need careful interpretation, health care professionals can utilise them to improve the delivery of personalised cancer care

Meta-analysis of factors associated with antidiabetic drug prescribing for Type 2 diabetes mellitus

Background: There is a lack of consensus on prescribing alternatives to initial metformin therapy and intensification therapy for type 2 diabetes mellitus (T2DM) management. This review aimed to identify/quantify factors associated with prescribing of specific antidiabetic drug classes for T2DM. Methods: Five databases (Medline/PubMed, Embase, Scopus, Web of Science) were searched using the synonyms of each concept (patients with T2DM, antidiabetic drugs, and factors influencing prescribing) in both free text and Medical Subject Heading (Mesh) forms. Quantitative observational studies evaluating factors associated with antidiabetic prescribing of metformin, sulfonylurea, thiazolidinedione, Dipeptidyl-peptidase 4 inhibitors (DPP4-I), sodium glucose transporter 2 inhibitors (SGLT2-I), Glucagon-Like peptide receptor agonist (GLP1-RA), and insulin in outpatient settings and published from January/2009 to January/2021 were included. Quality assessment was performed using a Newcastle-Ottawa scale. The validation was done for 20% of identified studies. The pooled estimate was measured using a three-level random-effect meta-analysis model based on odds ratio [95% confidence interval]. Age, sex, body mass index (BMI), glycaemic control (HbA1c), and kidney-related problems were quantified. Results: Of 2331 identified studies, forty met the selection criteria. Of which, 36 and 31 studies included sex and age, respectively, while 20 studies examined baseline BMI, HbA1c, and kidney-related problems. The majority of studies (77.5%, 31/40) were rated as good and despite that the overall heterogeneity for each studied factor was more than 75%, it is mostly related to within-study variance. Older age was significantly associated with higher sulfonylurea prescription (1.51[1.29-1.76]), yet lower prescribing of metformin (0.70[0.60-0.82]), SGLT2-I (0.57[0.42-0.79]), and GLP1-RA (0.52[0.40-0.69]); while higher baseline BMI showed opposite significant results (sulfonylurea: 0.76[0.62-0.93], metformin: 1.22[1.08-1.37], SGLT2-I: 1.88[1.33-2.68], and GLP1-RA: 2.35[1.54-3.59]). Both higher baseline HbA1c and having kidney-related problems were significantly associated with lower metformin prescription (0.74[0.57-0.97], 0.39[0.25-0.61]), but more insulin prescriptions (2.41[1.87-3.10], 1.52[1.52[1.10-2.10]). Also, DPP4-I prescriptions were higher for patients with kidney-related problems (1.37[1.06-1.79) yet lower among patients with higher HbA1c (0.82[0.68-0.99]. Sex was significantly associated with GLP1-RA and thiazolidinedione prescribing (F:M; 1.38[1.19-1.60] and 0.91[0.84-0.98). Conclusion: Several factors were identified as potential determinants of antidiabetic drug prescribing. The magnitude and significance of each factor differed by antidiabetic class. Patient’s age and baseline BMI had the most significant association with the choice of four out of the seven studied antidiabetic drugs followed by the baseline HbA1c and kidney-related problems which had an impact on three studied antidiabetic drugs, whereas sex had the least impact on prescribing decision as it was associated with GLP1-RA and thiazolidinedione only

Formulation and characterization of glipizide solid dosage form with enhanced solubility.

Glipizide, a poor water-soluble drug belongs to BCS class II. The proposed work aimed to enhance the solubility of glipizide by preparing solid dispersions, using polyvinyl pyrrolidone (PVP) and polyethylene glycol (PEG). Solvent evaporation method was used for the preparation of glipizide solid dispersions. Solid dispersions were prepared in four different drug-to-polymer ratios i.e. 1:1, 1:2, 1:3 and 1:4. Mainly effect of three polymers (PVP K30, PVP K90 and PEG 6000) was evaluated on the solubility and dissolution of glipizide. The in-vitro dissolution of all prepared formulations was performed under pH 6.8 at 37°C using USP type II apparatus. In-vitro dissolution results revealed that the formulations having high concentrations of the polymer showed enhanced solubility. Enhancements in the solubility and rate of dissolution of the drug were noted in solid dispersion formulations compared to the physical blends and pure drug. Solid dispersions containing polyvinyl pyrrolidone exhibited a more favorable pattern of drug release compared to the corresponding solid dispersions with PEG. An increase in the maximum solubility of the drug within the solid dispersion systems was observed in all instances. Two solid dispersion formulations were optimized and formulated into immediate-release tablets, which passed all the pharmacopoeial and non-pharmacopoeial tests. Fourier transformed Infrared (FTIR) spectroscopy X-ray diffraction (XRD) and Differential scanning calorimetry (DSC) were used to indicate drug: polymer interactions in solid state. Analysis of the solid dispersion samples through characterization tests indicated the compatibility between the drug and the polymer

Development of Orally Active Anti-Inflammatory Agents: In Vivo and In Silico Analysis of Naphthalene-Chalcone Derivatives Based on 2-Acetyl-6-Methoxy Naphthalene

Chalcone compounds are reported to have diverse biological activities such as antiviral, antimicrobial, antimalarial, antitumor, antifungal, anticancer, and so forth. Herewith, we wish to report the in-vivo anti-inflammatory activities of previously synthesized naphthalene-chalcone hybrids from 2-Acetyl-6-Methoxy Naphthalene derivatives (C1-C25). All synthesized chalcones (C1-C25) were thoroughly characterized with standard spectroscopic techniques and tested for their in-vivo anti-inflammatory activities. The currently employed in-silico docking methodology uses the ‘Molegro Virtual Docker’ as a docking tool and target proteins as COX-1 (PDB ID: 1EQH) and COX-2 (PDB ID: 1PXX). Molecular docking analysis of chalcones (C1-C25) suggested that compound C-24 exhibited b docking score of -117.495 kcal/mol than the standard flurbiprofen -115.259 kcal/mol on COX-1 target. To understand more about pharmacokinetics aspects, we predicted theoretical ADME properties using ‘QikProp, 2022’ and found that all compounds were exhibited acceptable pharmacokinetic properties

Development and characterisation of MMT-reinforced polyacrylonitrile-pullulan nanofibers for controlled permeation of isotretinoin

AbstractDrug nanofibers play a crucial role in ameliorating therapeutic effects, reducing toxicity, and increasing the bioavailability of drugs. This study was aimed at the fabrication of isotretinoin-loaded MMT-reinforced bi-polymeric (PAN/PU) nanofibers with varying concentrations of isotretinoin. In this study, montmorillonite (MMT)-reinforced cross-linked polyacrylonitrile and pullulan nanofibers combined with varying amounts of isotretinoin were fabricated through an electrospinning approach and investigated for their drug permeation potential. PAN-PU nanofibers were successfully integrated with the isotretinoin. The incorporation of isotretinoin into the nanofibrous structure was confirmed by FTIR and XRD. TGA study indicated the stability of the fabricated nanoparticles. The SEM results showed the beaded and smooth morphology of nanofibers. Formulation with a higher drug concentration had a non-significantly (p > 0.05) higher swelling ratio. Drug-loaded polymeric nanofiber erodes at a slower rate as compared to drug-free nanofibers. The ex-vivo permeation study of nanofibers revealed that the drug was not released all at once, but rather gradually and consistently over the period of 24 h, indicating a controlled release of the drug. In addition, the drug concentration in the nanofibers affected the permeation of the drug. According to the findings, isotretinoin-loaded MMT-reinforced bi-polymeric (PAN/PU) nanofibers with varying concentrations of isotretinoin were successfully fabricated. The fabricated nanofibers (PAN/PU) showed a promising potential for controlled permeation of drugs through rabbit skin

Development, Validation, and Utilization of a Social Media Use and Mental Health Questionnaire among Middle Eastern and Western Adults: A Pilot Study from the UAE

Objectives: We aimed to develop and validate a mental health stigma measurement tool for use within the social media context, utilizing the tool to assess whether the stigma shown in face-to-face interactions translates to social media, coupled with comparing whether social media use can cause the stigma among a sample of Middle Eastern and Western populations. Methods: The development and validation phase comprised a systematic process that was used to develop an assessment tool that could be used within the social media context and establish its validity and reliability. A 5-point Likert-type scale (1 = strongly disagree to 5 = strongly agree) was developed to assess mental health stigma. The anonymous questionnaire was distributed from June 2022 to August 2022 on various social media platforms and groups predominated by the two demographics of interest, enrolling 1328 participants (with only 1001 responses deemed valid). The utilization phase consisted of bivariate and multivariable analysis of the data. The cutoff points for low, medium, and high scores were the 25th, 50th, and 75th percentil, respectively. Results: The instrument comprised three dimensions: acceptance, intolerance, and digital care sentiment. In the Middle Eastern subset of participants, a higher score of intolerance (more stigma) toward mental illness was found in 72.4% of the participants, with a higher score of acceptance being 35.1% and of digital care sentiment being 46.4%. The mean scores for all the scales were as follows: intolerance (3.08 ± 0.64), acceptance (3.87 ± 0.71), and digital care sentiment (3.18 ± 0.69). For Westerners, a higher score of intolerance toward mental illness was found in 24.0% of the participants, with a higher score of acceptance being 56.8% and of digital care sentiment being 38.2%. The mean scores for all the scales were as follows: intolerance (2.28 ± 0.73), acceptance (4.21 ± 0.61), and digital care sentiment (3.08 ± 0.62). Various results were obtained regarding the effect of individual social media platforms on the different subscales. Conclusions: Stigma does follow people on social media, whether they are Middle Easterners or Westerners, although to varying degrees. The results of social media interaction and activity varied based on the group that used them, with some having an impact on one group but not the other. For these reasons, proper guidance is advised when utilizing and interacting with social media platforms

Photodynamic therapy: A special emphasis on nanocarrier-mediated delivery of photosensitizers in antimicrobial therapy

Resistance to antimicrobial drugs is an impending healthcare problem of growing significance. In the post-antibiotic era, there is a huge push to develop new tools for effectively treating bacterial infections. Photodynamic therapy involves the use of a photosensitizer that is activated by the use of light of an appropriate wavelength in the presence of oxygen. This results in the generation of singlet oxygen molecules that can kill the target cells, including cancerous cells and microbial cells. Photodynamic therapy is shown to be effective against parasites, viruses, algae, and bacteria. To achieve high antimicrobial activity, a sufficient concentration of photosensitizer should enter the microbial cells. Generally, photosensitizers tend to aggregate in aqueous environments resulting in the weakening of photochemical activity and lowering their uptake into cells. Nanocarrier systems are shown to be efficient in targeting photosensitizers into microbial cells and improve their therapeutic efficiency by enhancing the internalization of photosensitizers into microbial cells. This review aims to highlight the basic principles of photodynamic therapy with a special emphasis on the use of nanosystems in delivering photosensitizers for improving antimicrobial photodynamic therapy