A Genome-Wide Association Study of Oxypurinol Concentrations in Patients Treated with Allopurinol.

Cohort studies have identified several genetic determinants that could predict the clinical response to allopurinol. However, they have not been commonly used for genome-wide investigations to identify genetic determinants on allopurinol metabolism and concentrations. We conducted a genome-wide association study of a prior cross-sectional investigation of patients from the Montreal Heart Institute Biobank undergoing allopurinol therapy. Four endpoints were investigated, namely plasma concentrations of oxypurinol, the active metabolite of allopurinol, allopurinol, and allopurinol-riboside, as well as allopurinol daily dosing. A total of 439 participants (mean age 69.4 years; 86.4% male) taking allopurinol (mean daily dose 194.5 mg) and who had quantifiable oxypurinol concentrations were included in the genome-wide analyses. Participants presented with multiple comorbidities and received concomitant cardiovascular medications. No association achieved the predefined genome-wide threshold values for any of the endpoints (all p > 5 × 10-8). Our results are consistent with prior findings regarding the difficulty in identifying genetic determinants of drug concentrations or pharmacokinetics of allopurinol and its metabolites, as well as allopurinol daily dosing. Given the size of this genome-wide study, collaborative investigations involving larger and diverse cohorts may be required to further identify pharmacogenomic determinants of allopurinol and measure their clinical relevance to personalize allopurinol therapy.

Tophaceous gout.

Hyperuricemic patients (≥7.8 mg/dL) can develop polyarticular tophaceous gout from intermittent arthritis if untreated. Acute flares and tophi development can be avoided by lowering blood urate levels with xanthine oxidase inhibitors.

Efficacy and Safety of Allopurinol and Febuxostat in Patients With Gout and CKD: Subgroup Analysis of the STOP Gout Trial.

RATIONALE & OBJECTIVE: We conducted a prespecified examination of the efficacy and safety of allopurinol and febuxostat administered using a treat-to-target strategy in trial participants with chronic kidney disease (CKD). STUDY DESIGN: Prespecified sub cohort analysis of a randomized controlled trial. SETTING: & Participants: A sub study of the STOP Gout trial in participants with CKD. CKD was defined as an eGFR 30-59 mL/min/1.73 m2 at baseline. EXPOSURE: Trial participants with CKD and gout and serum urate (sUA) concentration ≥6.8 mg/dL were randomized 1:1 to receive allopurinol or febuxostat. Urate lowering therapy (ULT) was titrated during weeks 0-24 to achieve a goal sUA of <6.0 mg/dl (<5.0 mg/dl with tophi) (Phase 1) and maintained during weeks 25-48 (Phase 2). Gout flare was assessed between weeks 49-72 (Phase 3). OUTCOME: Gout flare between weeks 49-72 (Phase 3) was the primary outcome. Secondary outcomes included sUA goal achievement and ULT dosing at end of Phase 2, and serious adverse events (SAEs). ANALYTICAL APPROACH: Outcomes between treatment groups were compared using logistic regression models for binary outcomes, and Poisson regression for flare rates. Multivariable models were subsequently used, adjusting for factors identified to be imbalanced by treatment arm. RESULTS: 351 of 940 participants (37.3%) had CKD; 277 were assessed for the primary outcome. Fewer patients randomized to allopurinol had a flare during phase 3 (32% vs 45%; p=0.02) despite similar attainment of sUA goal (79% vs. 81%; p=0.6) by the end of Phase 2. Acute kidney injury (AKI) was more common in participants with stage 3 CKD randomized to allopurinol compared to febuxostat. LIMITATIONS: Limited power to assess infrequent safety events, largely male, older population. CONCLUSIONS: Allopurinol and febuxostat are similarly efficacious and well-tolerated in the treatment of gout in people with CKD when used in a treat-to-target regimen.

Assessment of Bitterness in Non-Charged Pharmaceuticals with a Taste Sensor: A Study on Substances with Xanthine Scaffold and Allopurinol.

Taste sensors with an allostery approach have been studied to detect non-charged bitter substances, such as xanthine derivatives, used in foods (e.g., caffeine) or pharmaceuticals (e.g., etofylline). In this study, the authors modified a taste sensor with 3-bromo-2,6-dihydroxybenzoic acid and used it in conjunction with sensory tests to assess the bitterness of non-charged pharmaceuticals with xanthine scaffolds (i.e., acefylline and doxofylline), as well as allopurinol, an analogue of hypoxanthine. The results show that the sensor was able to differentiate between different levels of sample bitterness. For instance, when assessing a 30 mM sample solution, the sensor response to acefylline was 34.24 mV, which corresponded to the highest level of bitterness (τ = 3.50), while the response to allopurinol was lowest at 2.72 mV, corresponding to relatively weaker bitterness (τ = 0.50). Additionally, this study extended the application of the sensor to detect pentoxifylline, an active pharmaceutical ingredient in pediatric medicines. These results underscore the taste sensor's value as an additional tool for early-stage assessment and prediction of bitterness in non-charged pharmaceuticals.

Association between urate-lowering therapy initiation and all-cause mortality in patients with type 2 diabetes and asymptomatic hyperuricemia.

AIMS: To assess the relationships between urate-lowering therapy (ULT) initiation with all-cause mortality in patients with asymptomatic hyperuricemia and Type 2 Diabetes (T2D). METHODS: This nationwide retrospective cohort study involved patients with T2D and asymptomatic hyperuricemia from 19 academic hospitals across China between 2000 and 2021. The primary exposure was ULT initiation, including allopurinol, febuxostat, or benzbromarone. The primary outcome was all-cause mortality. The secondary outcomes were cardiovascular (CV) and non-CV mortality. Propensity score matching was employed to create a 1:2 matched cohort with balanced likelihood of ULT initiation. Associations between ULT initiation with all-cause and CV mortality were assessed in the matched cohort. RESULTS: Among 42 507 patients, 5028 initiated ULT and 37 479 did not. In the matched cohort, comprising 4871 ULT initiators and 9047 noninitiators, ULT initiation was significantly associated with reduced risk of all-cause mortality (hazard ratio [HR] 0.77; 95% confidence interval [CI], 0.71-0.84), CV mortality (HR 0.86; 95% CI, 0.76-0.97), and non-CV mortality (HR 0.72; 95% CI, 0.64-0.80) over an average 3.0 years of follow-up. Among the ULT initiators, post-treatment SUA levels of 360-420 µmol/L was related to a significantly lower risk for all-cause mortality compared to levels >420 µmol/L (HR 0.74; 95% CI, 0.59-0.94) while levels ≤360 µmol/L did not (HR, 0.96; 95% CI, 0.81-1.14), suggesting a U-shaped relationship. CONCLUSIONS: Initiating ULT was associated with a significant reduction in all-cause mortality in patients with T2D and asymptomatic hyperuricemia. Notably, maintaining post-treatment SUA concentrations within 360-420 µmol/L could potentially enhance this reduced mortality.

Critically Appraised Topic on Canine Leishmaniosis: Does Treatment with Antimonials and Allopurinol Have the Same Clinical and Clinicopathological Efficacy as Treatment with Miltefosine and Allopurinol, after One Month of Treatment?

The treatment of canine leishmaniosis commonly involves meglumine antimoniate with allopurinol or miltefosine with allopurinol. This study aims to compare the clinical and clinicopathological efficacy at 28-30 days of conventional dosing regimens for both treatments using the critically appraised topic methodology. A comprehensive search across three databases (PubMed, CAB Abstracts, and Web of Science) from March 2004 to September 2023 yielded 16 relevant articles, encompassing 325 ogs treated with meglumine antimoniate and allopurinol, and 273 dogs treated with miltefosine and allopurinol. The findings indicated a significantly higher rate of complete clinical cure in the group treated with meglumine antimoniate and allopurinol. Most dogs in both groups exhibited improvement in clinicopathological alterations after one month of treatment. No significant difference was observed in the number of dogs that showed a negative Leishmania qPCR between the two groups, one month post-treatment. However, quantitative serology results were not commonly reported in the available data and therefore this aspect could not be compared.

Understanding the impact of ABCG2 polymorphisms on drug pharmacokinetics: focus on rosuvastatin and allopurinol.

INTRODUCTION: In addition to the well-established understanding of the pharmacogenetics of drug-metabolizing enzymes, there is growing data on the effects of genetic variation in drug transporters, particularly ATP-binding cassette (ABC) transporters. However, the evidence that these genetic variants can be used to predict drug effects and to adjust individual dosing to avoid adverse events is still limited. AREAS COVERED: This review presents a summary of the current literature from the PubMed database as of February 2024 regarding the impact of genetic variants on ABCG2 function and their relevance to the clinical use of the HMG-CoA reductase inhibitor rosuvastatin and the xanthine oxidase inhibitor allopurinol. EXPERT OPINION: Although there are pharmacogenetic guidelines for the ABCG2 missense variant Q141K, there is still some conflicting data regarding the clinical benefits of these recommendations. Some caution appears to be warranted in homozygous ABCG2 Q141K carriers when rosuvastatin is administered at higher doses and such information is already included in the drug label. The benefit of dose adaption to lower possible side effects needs to be evaluated in prospective clinical studies.

Linear solvent strength model on porous graphitic carbon stationary phase using high temperature liquid chromatographic method for allopurinol related substances analysis.

A high-performance liquid chromatography (HPLC) method was developed for the analysis of Allopurinol and its Ph.Eur. impurities using a porous graphitic carbon (PGC) stationary phase. Retention behavior of solutes was studied across a wide temperature range (30-90 °C) and various gradient times (5-20 min). Analysis of the data revealed distinct retention mechanisms between reversed-phase and PGC phases. However, it was proved that the retention of Allopurinol and its Ph.Eur. impurities on PGC stationary phase can be effectively modeled using the linear solvent strength (LSS) theory. This allows for the utilization of LSS-based method development software to optimize methods under these conditions. By using commercial chromatographic modeling software, separation of Allopurinol and Ph.Eur. impurities was optimized within a large design space. At the optimized operating conditions (pH = 2.0, tG = 6 min, T = 60 °C), all solutes were separated within 6 min with baseline resolution. Comparison between predicted and experimentally measured chromatograms further confirmed the applicability of LSS theory in developing analytical methods for PGC-based HPLC systems. The presented approach offers a general framework for method development on PGC phases.

The compelling role of allopurinol in hyperuricemia-induced epilepsy: Unrecognized like tears in rain.

Epilepsy is a common neurological disease characterized by the recurrent, paroxysmal, and unprovoked seizures. It has been shown that hyperuricemia enhances and associated with the development and progression of epilepsy through induction of inflammation and oxidative stress. In addition, uric acid is released within the brain and contributes in the development of neuronal hyperexcitability and epileptic seizure. Brain uric acid acts as damage associated molecular pattern (DAMP) activates the immune response and induce the development of neuroinflammation. Therefore, inhibition of xanthine oxidase by allopurinol may reduce hyperuricemia-induced epileptic seizure and associated oxidative stress and inflammation. However, the underlying mechanism of allopurinol in the epilepsy was not fully elucidated. Therefore, this review aims to revise from published articles the link between hyperuricemia and epilepsy, and how allopurinol inhibits the development of epileptic seizure.

Influence of xanthine oxidase inhibitors on all-cause mortality in adults: a systematic review and meta-analysis.

Xanthine oxidase inhibitors, including allopurinol and febuxostat, are the first-line treatment of hyperuricemia. This meta-analysis investigated the association between urate-lowering therapy and all-cause mortality in different chronic diseases to match its users and non-users in a real-world setting. Overall, 11 studies were included, which reported adjusted hazard ratios for all-cause mortality over at least 12 months. Meta-analysis of all included studies showed no effect of the therapy on all-cause mortality. However, subgroup analyses showed its beneficial effect in patients with chronic kidney disease (14% risk reduction) and hyperuricemia (14% risk reduction), but not in patients with heart failure (28% risk increase). Urate-lowering therapy reduces all-cause mortality among patients with hyperuricemia and chronic kidney disease, but it seems to increase mortality in patients with heart failure and should be avoided in this subgroup.

Effective xanthine oxidase inhibitor urate lowering therapy in gout is linked to an emergent serum protein interactome of complement activation and inflammation modulators.

Background: Urate-lowering treatment (ULT) to target with xanthine oxidase inhibitors (XOIs) paradoxically causes early increase in gouty arthritis flares. Because delayed reduction in flare burden is mechanistically unclear, we tested for ULT inflammation responsiveness markers. Methods: Unbiased proteomics analyzed blood samples (baseline, 48 weeks ULT) in two, independent ULT out trial cohorts (n = 19, n = 30). STRING-db and multivariate analyses supplemented determinations of altered proteins via Wilcoxon matched pairs signed rank testing in XOI ULT responders. Mechanistic studies characterized proteomes of cultured XOI-treated murine bone marrow macrophages (BMDMs). Results: At 48 weeks ULT, serum urate normalized in all gout patients, and flares declined, with significantly altered proteins (p < 0.05) in clustering and proteome networks in sera and peripheral blood mononuclear cells. Serum proteome changes included decreased complement C8 heterotrimer C8A and C8G chains and chemokine PPBP/CXCL7, and increased urate crystal phagocytosis inhibitor sCD44. In both cohorts, a treatment-emergent serum interactome included key gouty inflammation mediators (C5, IL-1B, CXCL8, IL6). Last, febuxostat inhibited complement activation pathway proteins in cultured BMDMs. Conclusions: Reduced gout flares are kinked with a XOI-treatment emergent complement- and inflammation-regulatory serum protein interactome. Serum and leukocyte proteomes could help identify onset of anti-inflammatory responsiveness to ULT in gout. Trial registration: ClinicalTrials.gov Identifier: NCT02579096, posted October 19, 2015.

Mass Spectrometric Analysis of Purine Intermediary Metabolism Indicates Cyanide Induces Purine Catabolism in Rabbits.

Purines are the building blocks of DNA/RNA, energy substrates, and cofactors. Purine metabolites, including ATP, GTP, NADH, and coenzyme A, are essential molecules in diverse biological processes such as energy metabolism, signal transduction, and enzyme activity. When purine levels increase, excess purines are either recycled to synthesize purine metabolites or catabolized to the end product uric acid. Purine catabolism increases during states of low oxygen tension (hypoxia and ischemia), but this metabolic pathway is incompletely understood in the context of histotoxic hypoxia (i.e., inhibition of oxygen utilization despite normal oxygen tension). In rabbits exposed to cyanide-a classical histotoxic hypoxia agent-we demonstrated significant increases in several concordant metabolites in the purine catabolic pathway (including plasma levels of uric acid, xanthosine, xanthine, hypoxanthine, and inosine) via mass spectrometry-based metabolite profiling. Pharmacological inhibition of the purine catabolic pathway with oxypurinol mitigated the deleterious effects of cyanide on skeletal muscle cytochrome c oxidase redox state, measured by non-invasive diffuse optical spectroscopy. Finally, plasma uric acid levels correlated strongly with those of lactic acid, an established clinical biomarker of cyanide exposure, in addition to a tissue biomarker of cyanide exposure (skeletal muscle cytochrome c oxidase redox state). Cumulatively, these findings not only shed light on the in vivo role(s) of cyanide but also have implications in the field of medical countermeasure (MCM) development.

Management of hypertension addressing hyperuricaemia: introduction of nano-based approaches.

Uric acid (UA) levels in blood serum have been associated with hypertension, indicating a potential causal relationship between high serum UA levels and the progression of hypertension. Therefore, the reduction of serum UA level is considered a potential strategy for lowering and mitigating blood pressure. If an individual is at risk of developing or already manifesting elevated blood pressure, this intervention could be an integral part of a comprehensive treatment plan. By addressing hyperuricaemia, practitioners may subsidize the optimization of blood pressure regulation, which illustrates the importance of addressing UA levels as a valuable strategy within the broader context of hypertension management. In this analysis, we outlined the operational principles of effective xanthine oxidase inhibitors for the treatment of hyperuricaemia and hypertension, along with an exploration of the contribution of nanotechnology to this field.

Risk of urolithiasis associated with allopurinol versus benzbromarone among patients with gout: a population-based cohort study.

OBJECTIVES: To compare the risk of urolithiasis in gout patients initiating allopurinol, a xanthine oxidase inhibitor, vs benzbromarone, a uricosuric. METHODS: Using the 2011-2020 Korea National Health Insurance Service database, we conducted a cohort study on gout patients initiating allopurinol vs benzbromarone as the 1st-line urate-lowering treatment (ULT). The primary outcome was a new onset urinary stone. The secondary outcome was a stone requiring intervention. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazard models with a 5:1 ratio propensity-score matching on > 80 variables. Subgroup analyses were done by age, sex, thiazide use, and cardiovascular (CV) risk. RESULTS: 61 300 allopurinol initiators PS-matched on 12 260 benzbromarone initiators were included (mean age 59 years, 79% male). During a mean follow-up of 322 days, 619 urolithiasis cases occurred with an incidence rate of 0.87 per 100 person-years in allopurinol and 1.39 in benzbromarone initiators, showing a HR of 0.64 (95% CI, 0.51-0.80). ∼44% of urinary stones required intervention with a HR of 0.61 (95% CI 0.43-0.88). The lower risk associated with allopurinol compared with benzbromarone persisted across subgroups but was greater in the high than non-high CV risk subgroup (p for interaction = 0.02). CONCLUSION: This population-based cohort study found that allopurinol compared with benzbromarone was associated with a substantially lower risk of urolithiasis particularly in the presence of the high CV risk. This finding provides important safety information for clinicians' decision-making on ULTs of different mechanisms of action.

Tumor lysis syndrome in induction therapy for acute myeloid leukemia before the rasburicase era.

Guidelines recommend rasburicase for high-risk patients to prevent tumor lysis syndrome (TLS). However, little information is available on the incidence and outcome of TLS in AML patients. We analyzed 145 patients with AML who underwent induction therapy before the approval of rasburicase to evaluate the incidence of TLS and the necessity of rasburicase as prophylaxis. Three patients had already developed clinical TLS (CTLS) at diagnosis of AML, and another three developed CTLS after the initiation of chemotherapy. In patients without TLS at diagnosis of AML, the risk for developing TLS was classified as high in 44 patients, intermediate in 41 and low in 57, according to the current guidelines. Allopurinol alone was administered to prevent hyperuricemia in all patients. All three patients who developed CTLS after diagnosis of AML were at high risk of TLS, and had elevated serum creatinine levels and a WBC count greater than 200,000 per microliter at diagnosis of AML. Allopurinol may be insufficient to prevent TLS in high-risk patients with renal dysfunction at diagnosis of AML, especially those with a high tumor burden and a WBC count of 200,000 or more, which indicates that prophylactic administration of rasburicase should be considered.

A Rare Pediatric Case of Allopurinol-Induced Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) Successfully Treated With Intravenous Immunoglobulins.

Allopurinol-induced drug reaction syndrome with eosinophilia and systemic symptoms (A-DRESS) is a well-described condition in adults, whereas it is uncommon among children. We describe a case of A-DRESS in a 16-year-old male with steroid-dependent nephrotic syndrome. He presented a life-threatening clinical course with persisting fever, skin rash, eosinophilia, lymphadenopathy, distributive shock, and herpesvirus 6 detection. The withdrawal of allopurinol and a combination of intravenous immunoglobulins (IVIGs) and systemic corticosteroids led to the patient's recovery without sequelae. Drug reaction with eosinophilia and systemic symptoms (DRESS) in pediatrics is rare and can present in a severe form. Early diagnosis and timely treatment are critical for prognostic purposes. This report suggests the potentially crucial role of IVIG in the treatment of patients with A-DRESS.

Fatal Itching and Failing Liver: A Case Report and Literature Review of Rare, Atypical DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) Syndrome.

DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome is a rare, life-threatening, hypersensitivity reaction. The prolonged course and non-specific symptoms of the condition make diagnosis challenging. We present a case of DRESS syndrome that was misdiagnosed as urticaria. Investigations revealed deranged liver and kidney functions and abnormal blood count. The presented case emphasizes the need to have a high suspicion for DRESS syndrome in patients who present with jaundice, generalized rash, acute renal failure, and acute liver failure.

Urate-lowering therapy is associated with a reduced risk of arrhythmias: a systematic review and meta-analysis.

Objective: While urate-lowering therapy (ULT) is linked to increased cardioprotective benefits on primary prevention of cardiovascular events such myocardial infarction or heart failure, little is known regarding their effects on arrhythmia risk. The purpose of this study was to investigate the relationship between incident arrhythmias and ULT. Methods: We searched MEDLINE and Embase from inception to May 2023. Included studies were randomized controlled trials and cohort studies that compared the risk of cardiac arrhythmias among ULT users with non-ULT users. Results: A total of 12,420 patients from five studies were analyzed, comprising 7,359 subjects in the ULT group and 5,061 subjects in the non-ULT group. Our results showed that ULT users had significant reductions in the risk of arrhythmias (pooled relative risk [RR] 0.82, 95% confidence interval [CI] 0.74~0.92, p<0.001, I2=0.0%) compared to non-ULT users. Subgroup analysis did not show that ULT users had a significant reduced risk of atrial fibrillation (pooled RR 0.76, 95% CI 0.54~1.05, p=0.096 with I2=15.4%) compared to non-ULT users. Conclusion: ULT is associated with lower risk of overall arrhythmias. Further studies are warranted to confirm our findings.

Influence of pharmacogenomic polymorphisms on allopurinol-induced cutaneous adverse drug reactions in Thai patients.

BACKGROUND: Allopurinol has been causing substantial morbidity and mortality particularly in Asian population by producing cutaneous adverse drug reactions (cADRs). Nonetheless, there are no data describing whether other genetics are a valid marker for prediction of allopurinol-induced cADRs patients in addition to HLA-B*58:01 allele. The goal of this study was to identify suitable single nucleotide polymorphisms (SNPs) for allopurinol induced cADRs among Thai patients. METHODS: We conducted a case-control association study after enrolling 57 Thai patients with allopurinol induced cADRs and 101 allopurinol-tolerant controls. The genetic biomarkers and associated SNPs located on chromosome 6p21 were examined by TaqMan® SNP genotyping assays in both the cases and the controls. RESULTS: Out of fifteen SNPs in nine genes, we found four combined SNPs (rs3099844 of HCP5, rs9263726 of PSORS1C1, rs9263733 of POLR2LP, and rs9263745 of CCHCR1) were significantly associated with allopurinol-induced cADRs compared to the tolerant controls (OR 73.2; 95% CI 24.2-266.8; P = 1.9 × 10- 24). The overall sensitivity, specificity, positive predictive value and negative predictive value of these combinations were 84%, 94%, 9%, and 100%, respectively. However, the variant alleles of these SNP combinations were detected in 89.5% (51/57) of the cases. Moreover, the HLA-B*58:01 allele was observed in 86.0% of patients with allopurinol-induced cADRs, but only in 4.0% of tolerant controls (OR: 137.2; 95% CI: 38.3-670.5 and p-value = 1.7 × 10- 27). CONCLUSIONS: Thus, this research confirms the association between the specific HLA-B*58:01 allele and all phenotypes of allopurinol-induced cADRs in Thais. Furthermore, there was found the combined four SNPs (rs3099844, rs9263726, rs9263733, and rs9263745) could be used as alternative novel biomarkers for predicting cADRs in patients taking allopurinol.

Effect of uric acid reduction on chronic kidney disease. Systematic review and meta-analysis.

Accumulating evidence suggests that hyperuricemia is a pathological factor in the development and progression of chronic kidney disease. However, the potential benefit afforded by the control of uric acid (UA) is controversial. Individual studies show discrepant results, and most existing meta-analysis, especially those including the larger number of studies, lack a placebo or control group as they aim to compare efficacy between drugs. On these grounds, we performed a me-ta-analysis restricted to studies including the action of any anti-gout therapies referenced to a control or placebo arm. This approach allows for a clearer association between UA reduction and renal effect. Of the twenty-nine papers included, most used allopurinol and febuxostat and, therefore, solid conclusions could only be obtained for these drugs. Both were very effective in reducing UA, but only allopurinol was able to significantly improve glomerular filtration rate (GFR), although not in a dose-dependent manner. These results raised doubts as to whether it is the hypouricemic effect of anti-gout drugs, or a pleiotropic effect, what provides protection of kidney function. Accordingly, in a correlation study that we next performed between UA reduction and GFR improvement, no association was found, which suggests that additional mechanisms may be involved. Of note, most trials show large inter-individual response variability, probably because they included patients with heterogeneous phenotypes and pathological characteristics, including different stages of CKD and comorbidities. This highlights the need to sub classify the effect of UA-lowering therapies according to the pathological scenario, in order to identify those CKD patients that may benefit most from them. Systematic Review Registration: CRD42022306646 https://www.crd.york.ac.uk/prospero/.