Metabolomic investigation of antihypertensive drug response. Studies of antihypertensive treatment adherence using targeted/untargeted drug screening in tertiary care hypertension patients

Hypertension is a major risk factor for several cardiovascular CV diseases. The estimated prevalence of HTN in Scotland in the adult population from 2014 to 2017 for all age groups in both sexes was 58.7%. Medication adherence is assessed using 2 different methods, either indirect or direct methods each has its own advantages and disadvantages. Non-adherence to therapy can lead to uncontrolled blood pressure (BP), deterioration in health and progression of disease state. It can also increase the cost burden on the health care system. The main aim of this study was to assess adherence by indirect methods using the self-reported Morrisby Medication Adherence Scale (MMAS-8) and direct method by untargeted and targeted drug screening in urine samples of hypertensive patients attending Glasgow Blood Pressure clinic (GBPC). Drug screening was analysed using 3 assays: First, Birmingham heartland laboratory BIR using HP LC-MS/MS. Second, Glasgow Polynomic POL using untargeted mass spectrometry data-dependent fragmentation spectra and molecular approach (based on Hydrophilic interaction liquid chromatography. Finally, Glasgow toxicology GLA using Hollow-fibre liquid-phase microextraction followed by LC-MS/MS for 10 antihypertensive drugs. 348 patients completed Morrisby questionnaire and showed that 62.1% of patients had high adherence, while 26.7% of patients had medium adherence and only 11.2 had low adherence. Despite the high adherence detected, the level of BP control was low. Only 35% of patient who reported that they were adherent had controlled SBP. 79 urine samples were sent to Birmingham heartland laboratory and the assay was able to detect complete presence of antihypertensive medication in 49 (62%) of the urine samples. Only 6 (7.6%) samples were found to be completely absent of any medication and the remaining (30.4%) detected at least one of the prescribed antihypertensive medications (partial). No drugs were detected in patients who weren’t prescribed them. 100 urine samples were sent to Glasgow Polyomics and was able to detect complete presence of antihypertensive medication in for most drugs it tested of the urine samples. 12 (12%) were completely absent of any medication. There was one false positive result. Out 173 urine samples sent to Glasgow toxicology 152 samples were tested for their prescribed drugs. Results showed only 6 (3.9%) patients weren’t detected for any medication in the sample, while 137 (89.5%) detected all the medication they were tested for and 9 (5.9%) had some their prescribed drugs detected (partial adherence). There was one false positive result. 57 samples were shared between the 3 assays for 4 antihypertensive drugs (Amlodipine, Atenolol, Losartan and Ramipril). Losartan was detected for all patient. Birmingham was the lowest method to detect amlodipine and atenolol. However, for Ramipril Birmingham identified more than the others. Glasgow Polyomics and Glasgow toxicology had high sensitivity for drugs around (80%). Glasgow Polyomics misidentified 1 patient that was prescribed metoprolol for atenolol. 79 patients were shared between Birmingham and Glasgow toxicology and were compared. Both methods agreed for most of the patients except GLA detected more for amlodipine and atenolol while Birmingham detected 1 more patient for Spironolactone. Analyses of the concentrations found by GLA doesn’t suggest those detected by GLA but not detected by BIR had lower concentrations. My study clearly shows no correlation between the Morisky score and adherence based on urine drug assays. The relationship between medication adherence and BP control is difficult to demonstrate. Adherence is an important and complex area of research that is essential to improve hypertension management and decrease the global burden of hypertension

Antihypertensive Drugs and Risk of Cancer: A Systematic Review and Meta-Analysis of 391, 790 Patients

Introduction: The potential risk of cancer associated with antihypertensive drugs has been disputed for decades as additional outcomes from randomized controlled trials (RCTs), observational studies, and meta-analyses showed conflicting results. Objective: To assess the risk of cancer in patients exposed to major antihypertensive drug classes. Methods: We searched bibliographic databases for RCTs published between 1950 to December 2015 studying angiotensin-receptor blockers (ARB), angiotensin-converting enzyme inhibitors (ACEi), beta-blockers (BB), calcium channel blockers (CCB), and thiazide diuretics (TZ). RCTs with at least one year duration of planned active treatment and a minimum of 100 participants per treatment arm were eligible. Main Outcome Measures: Cancer and cancer-related deaths from the RCTs. Both fixed-effect and random-effects models were conducted and results were expressed as odds ratio (OR). Results: We identified 91 RCTs enrolling 391, 790 participants with an average follow-up of 3.4 years. There was no evidence of excess risk for cancer with ARB, ACEi, BB, and TZ (refer Fig.1). For CCBs, there was an increased risk of cancer (OR 1.07 95%CI 1.02, 1.1) with minimal heterogeneity (I2=13%). Subgroup analysis did not differ significantly between dihydropyridines (DHP) and non-dihiydropyridines subclasses. There was no statistically significant association between antihypertensive drug classes and risk of cancer deaths. Conclusions: Our results suggest that ARB, ACEi, BB, and TZ are not associated with increased risk of cancer. CCB therapy shows an increased risk of cancer. Further investigation on the risk of cancer with CCB is warranted

The Effect of Coenzyme Q10 on Liver Injury Induced by Valproic Acid and Its Antiepileptic Activity in Rats

Valproic acid (VPA) has toxic metabolites that can elevate oxidative stress markers, and the hepatotoxicity of VPA has been reported. Coenzyme Q10 (CoQ10) is one of the most widely used antioxidants. The effect of CoQ10 on epileptogenesis and VPA hepatotoxicity were examined. Rats were randomly divided into five groups: the control group received 0.5% methylcellulose by oral gavages daily and saline by intraperitoneal injection three times weekly. The PTZ group received 1% methylcellulose by gavages daily and 30 mg/kg PTZ by intraperitoneal injection three times weekly. The valproic acid group received 500 mg/kg valproic acid by gavage and 30 mg/kg PTZ, as above. The CoQ10 group received 200 mg/kg CoQ10 by gavages daily and 30 mg/kg PTZ, as above. The Valproic acid + CoQ10 group received valproic acid and CoQ10, as above. Results: CoQ10 exhibited anticonvulsant activity and potentiated the anticonvulsant effect of VPA. CoQ10 combined with VPA induced a more significant reduction in oxidative stress and improved the histopathological changes in the brain and liver compared to VPA treatment. In addition, CoQ10 reduced the level of toxic VPA metabolites. These findings suggest that the co-administration of CoQ10 with VPA in epilepsy might have therapeutic potential by increasing antiepileptic activity and reducing the hepatotoxicity of VPA

Effect of Vitamin K on Bone Mineral Density and Fracture Risk in Adults: Systematic Review and Meta-Analysis

Summary: Recent studies have proposed that adequate intake of Vitamin K (VK) is associated with a low risk of fracture and high bone mineral density (BMD) to improve skeletal health in adults. This systematic review was designed to summarize the most relevant and updated evidence discussing the relationship between VK and bone. It explores the effect of VK deficiency and its supplementation on various bone parameters. Methods: The distinct databases such as PubMed, the Cochrane Library, Google Scholar, National Clinical Trials, Current Controlled Trials, and Clinical Trials were searched up to Jan 2020 to identify eligible trials. All relevant randomized controlled trial studies with any oral dosage form of VK supplement administered for at least six months and assessing BMD or fracture in adults were extracted. Finally, two independent reviewers identified 20 relevant citations for the systematic review and extracted data in tabular form. Results: The meta-analysis was performed with all studies, including postmenopausal and osteoporotic females, for both total clinical and vertebral fracture outcomes. The quantitative analysis showed that the odds ratios (OR) of any fracture were lower for VK as compared to control [OR 0.42 (95% CI 0.27 to 0.66)] for vertebral fractures and OR of 0.44 (95% CI 0.23 to 0.88) for clinical fracture. For the BMD, a meta-analysis of the pooled effect of interventional studies suggested a non-significant association between the use of VK and improvement in femoral BMD (CI 95%, p = 0.08 [−0.03–0.20]). Conclusion: VK decreases general fracture risk, and it can be an option to counter bone loss disorders. However, insufficient evidence is available regarding the significant impact of VK on femoral neck BMD. Therefore, further studies are required to establish the therapeutic value of VK as a treatment for osteoporosis

Urolithin A’s Antioxidative, Anti-Inflammatory, and Antiapoptotic Activities Mitigate Doxorubicin-Induced Liver Injury in Wistar Rats

Human colon microbiota produce a metabolite called urolithin A (URO A) from ellagic acid and linked compounds, and this metabolite has been demonstrated to have antioxidant, anti-inflammatory, and antiapoptotic activities. The current work examines the various mechanisms through which URO A protects against doxorubicin (DOX)-induced liver injury in Wistar rats. In this experiment, Wistar rats were administered DOX intraperitoneally (20 mg kg−1) on day 7 while given URO A intraperitoneally (2.5 or 5 mg kg−1 d−1) for 14 days. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyl transferase (GGT) were measured. Hematoxylin and eosin (HE) staining was used to evaluate histopathological characteristics, and then antioxidant and anti-inflammatory properties were evaluated in tissue and serum, respectively. We also looked at how active caspase 3 and cytochrome c oxidase were in the liver. The findings demonstrated that supplementary URO A therapy clearly mitigated DOX-induced liver damage. The antioxidant enzymes SOD and CAT were elevated in the liver, and the levels of inflammatory cytokines, such as TNF-α, NF-kB, and IL-6, in the tissue were significantly attenuated, all of which complemented the beneficial effects of URO A in DOX-induced liver injury. In addition, URO A was able to alter the expression of caspase 3 and cytochrome c oxidase in the livers of rats that were subjected to DOX stress. These results showed that URO A reduced DOX-induced liver injury by reducing oxidative stress, inflammation, and apoptosis

The use of therapeutic drug monitoring for early identification of vedolizumab response in Saudi Arabian patients with inflammatory bowel disease

Abstract Vedolizumab is a humanized monoclonal antibody used to treat moderate-to-severe inflammatory bowel disease (IBD). The aim of the study was to assess the effectiveness of the induction of vedolizumab trough level in predicting short-term (week 14) clinical outcomes, and covariates that affect the response in Saudi Arabian patients. This prospective, real-life study included a total of 16 patients (4 Crohn's disease (CD) and 12 ulcerative colitis (UC)) with a confirmed diagnosis of IBD and generally naïve to receiving vedolizumab therapy. Using ELISA assay, vedolizumab induction trough and peak levels were measured at weeks 0, 2, and 6. The follow-up assessment was at week 14, where clinical outcomes were measured using the partial Mayo score for UC, and the CD activity score (CDAI), and Harvey Bradshaw index (HBI) for CD. At week 14, 9 patients (52.9%) out of 16 patients demonstrated response to therapy; clinical remission was reported in 5 patients (29.4%), and in 4 cases a clinical response was noted (23.5%). Clinical remission at week 14 was linked significantly with week 6 median vedolizumab levels in responders (25.1 µg/ml 95% CI: 16.5–42.9) compared to non-responders (7.7 µg/ml, 95% CI: 4.6–10.6) (P = 0.002). Receiver operator curve analysis at week 6 identified a cut-off > 8.00 µg/mL for short-term clinical remission. Also, at week 14, BMI significantly correlated with week 6 vedolizumab trough levels (P = 0.02). No other covariates correlated with drug levels at any time point examined. Week 6 early vedolizumab trough level measurements in IBD patients predicted short-term week 14 clinical remission

Exploring the Antifungal Activity and Action of Saussurea costus Root Extracts against Candida albicans and Non-albicans Species

The isolation and assessment of the active constituents in polar and non-polar crude extracts of Saussurea costus roots as antifungal agents, against Candida albicans and non-C. albicans (NAC) species, was the aim of this current investigation. The SEM “Scanning electron microscopy” imaging provided potential action modes of n-hexane extract (nhhE) toward Candida spp., whereas the TLC-DB “Thin layer chromatography-direct bioautography” was employed for detecting the anticandidal compounds. nhhE had the greatest biocidal activity against all strains and clinical isolates of Candida spp. with maximum zones of inhibition. SEM revealed the occurrence of irregular, dense inclusions of C. albicans cell walls after treatment with nhhE for 12 h. Complete morphological distortions with lysed membranes and deterioration signs appeared in most treated cells of C. parapsilosis. The most effectual compound with anticandidal activity was isolated using TLC-BD and identified as sesquiterpene by GC/MS analysis. The infra-red analysis revealed the presence of lactone ring stretching vibrations at 1766.72 cm−1. The anticandidal activity of nhhE of S. costus roots was confirmed from the results, and the treated cotton fabrics with nhhE of S. costus possessed observable activity against C. albicans. Data could recommend the practical usage of S. costus extracts, particularly nhhE, as influential natural bioactive sources for combating pathogenic Candida spp

Association of Polymorphism of the Methyl Tetrahydrofolate Reductase (MTHFR) Gene with Anti-Seizure Medication Response in Pediatric Patients in Jeddah, Saudi Arabia

Background and Objectives: Epilepsy is a chronic brain disease, with inherent and noninherent factors. Although over 20 anti-seizure medications (ASMs) are commercially available, nearly one-third of patients develop drug-resistant epilepsy. We evaluated the association between the clinical features and the methyl tetrahydrofolate (MTHFR) rs1801133 polymorphism and ASMs response among pediatric patients with epilepsy. Materials and Methods: This was a multicenter, retrospective, case–control study of 101 children with epilepsy and 59 healthy children in Jeddah. The MTHFR rs1801133 polymorphism was genotyped using the real-time polymerase chain reaction TaqMan Genotyping Assay. Results: Among the patients with epilepsy, 56 and 45 showed good and poor responses to ASMs, respectively. No significant genetic association was noted between the single-nucleotide polymorphism (SNP) rs1801133 within the MTHFR gene and the response to ASMs. However, a significant association was noted between reports of drug-induced toxicity and an increase in allele A frequencies. The MTHFR rs1801133 genotype was significantly associated with the development of electrolyte disturbance among good and poor responders to ASMs. Conclusions: This is the first pharmacogenetic study of MTHFR in patients with epilepsy in Saudi Arabia that found no significant association between the MTHFR SNP rs1801133 and gene susceptibility and drug responsiveness. A larger sample size is needed for testing gene polymorphisms in the future

Nephroprotective effects of Acacia senegal against aflatoxicosis via targeting inflammatory and apoptotic signaling pathways

Aflatoxin B1 (AFB1) is a common environmental pollutant that poses a major hazard to both humans and animals. Acacia senegal (Gum) is well-known for having antioxidant and anti-inflammatory bioactive compounds. Our study aimed to scout the nephroprotective effects of Acacia gum (Gum) against AFB1-induced renal damage. Four groups of rats were designed: Control, Gum (7.5 mg/kg), AFB1 (200 µg/kg b.w) and AFB1-Gum, rats were co-treated with both Gum and AFB1. Gas chromatography-mass spectrometry (GC/MS) analysis was done to determine the phytochemical constituents in Gum. AFB1 triggered profound alterations in kidney function parameters (urea, creatinine, uric acid, and alkaline phosphatase) and renal histological architecture. Additionally, AFB1 exposure evoked up-regulation of mRNA expression levels of inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor α (TNFα), inducible nitric oxide synthase (iNOS), and nuclear factor kB p65 (NF-κB/P65) in renal tissue. The oxidative distress and apoptotic cascade are also instigated by AFB1 intoxication as depicted in down-regulated protein expression of the nuclear factor erythroid 2–related factor 2 (Nrf2) and superoxide dismutase type 1 (SOD1) along with upregulation of cytochrome c (Cyto c), and cleaved Caspase3 (Casp3–17 and 19) in renal tissue. In conclusion, current study obviously confirms the alleviating effects of Gum supplementation against AFB1-induced renal dysfunction, oxidative harm, inflammation, and cell death. These mitigating effects are suggested to be attributed to Gum's antioxidant and anti-inflammatory activities. Our results recommend Gum supplementation as add-on agents to food that might aid in protection from AFB1-induced nephrotoxicity

Arabic Gum Could Alleviate the Aflatoxin B1-provoked Hepatic Injury in Rat: The Involvement of Oxidative Stress, Inflammatory, and Apoptotic Pathways

Aflatoxin B1 (AF) is an unavoidable environmental pollutant that contaminates food, feed, and grains, which seriously threatens human and animal health. Arabic gum (AG) has recently evoked much attention owing to its promising therapeutic potential. Thus, the current study was conducted to look into the possible mechanisms beyond the ameliorative activity of AG against AF-inflicted hepatic injury. Male Wistar rats were assigned into four groups: Control, AG (7.5 g/kg b.w/day, orally), AF (200 µg/kg b.w), and AG plus AF group. AF induced marked liver damage expounded by considerable changes in biochemical profile and histological architecture. The oxidative stress stimulated by AF boosted the production of plasma malondialdehyde (MDA) level along with decreases in the total antioxidant capacity (TAC) level and glutathione peroxidase (GPx) activity. Additionally, AF exposure was associated with down-regulation of the nuclear factor erythroid2–related factor2 (Nrf2) and superoxide dismutase1 (SOD1) protein expression in liver tissue. Apoptotic cascade has also been evoked following AF-exposure, as depicted in overexpression of cytochrome c (Cyto c), cleaved Caspase3 (Cl. Casp3), along with enhanced up-regulation of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, inducible nitric oxide synthase (iNOS), and nuclear factor kappa-B transcription factor/p65 (NF-κB/p65) mRNA expression levels. Interestingly, the antioxidant and anti-inflammatory contents of AG may reverse the induced oxidative damage, inflammation, and apoptosis in AF-exposed animals