Vitamin K: a potential missing link in critical illness-a scoping review.

BACKGROUND: Vitamin K is essential for numerous physiological processes, including coagulation, bone metabolism, tissue calcification, and antioxidant activity. Deficiency, prevalent in critically ill ICU patients, impacts coagulation and increases the risk of bleeding and other complications. This review aims to elucidate the metabolism of vitamin K in the context of critical illness and identify a potential therapeutic approach. METHODS: In December 2023, a scoping review was conducted using the PRISMA Extension for Scoping Reviews. Literature was searched in PubMed, Embase, and Cochrane databases without restrictions. Inclusion criteria were studies on adult ICU patients discussing vitamin K deficiency and/or supplementation. RESULTS: A total of 1712 articles were screened, and 13 met the inclusion criteria. Vitamin K deficiency in ICU patients is linked to malnutrition, impaired absorption, antibiotic use, increased turnover, and genetic factors. Observational studies show higher PIVKA-II levels in ICU patients, indicating reduced vitamin K status. Risk factors include inadequate intake, disrupted absorption, and increased physiological demands. Supplementation studies suggest vitamin K can improve status but not normalize it completely. Vitamin K deficiency may correlate with prolonged ICU stays, mechanical ventilation, and increased mortality. Factors such as genetic polymorphisms and disrupted microbiomes also contribute to deficiency, underscoring the need for individualized nutritional strategies and further research on optimal supplementation dosages and administration routes. CONCLUSIONS: Addressing vitamin K deficiency in ICU patients is crucial for mitigating risks associated with critical illness, yet optimal management strategies require further investigation. IMPACT RESEARCH: To the best of our knowledge, this review is the first to address the prevalence and progression of vitamin K deficiency in critically ill patients. It guides clinicians in diagnosing and managing vitamin K deficiency in intensive care and suggests practical strategies for supplementing vitamin K in critically ill patients. This review provides a comprehensive overview of the existing literature, and serves as a valuable resource for clinicians, researchers, and policymakers in critical care medicine.

Is a Vitamin K Epoxide Reductase Complex Subunit 1 (VKORC1) Polymorphism a Risk Factor for Nephrolithiasis in Sarcoidosis?

Sarcoidosis is a systemic inflammatory disorder characterized by granuloma formation in various organs. It has been associated with nephrolithiasis. The vitamin K epoxide reductase complex subunit 1 (VKORC1) gene, which plays a crucial role in vitamin K metabolism, has been implicated in the activation of proteins associated with calcification, including in the forming of nephrolithiasis. This study aimed to investigate the VKORC1 C1173T polymorphism (rs9934438) in a Dutch sarcoidosis cohort, comparing individuals with and without a history of nephrolithiasis. Retrospectively, 424 patients with sarcoidosis were divided into three groups: those with a history of nephrolithiasis (Group I: n = 23), those with hypercalcemia without nephrolithiasis (Group II: n = 38), and those without nephrolithiasis or hypercalcemia (Group III: n = 363). Of the 424 sarcoidosis patients studied, 5.4% had a history of nephrolithiasis (Group I), only two of whom possessed no VKORC1 polymorphisms (OR = 7.73; 95% CI 1.79-33.4; p = 0.001). The presence of a VKORC1 C1173T variant allele was found to be a substantial risk factor for the development of nephrolithiasis in sarcoidosis patients. This study provides novel insights into the genetic basis of nephrolithiasis in sarcoidosis patients, identifying VKORC1 C1173T as a potential contributor. Further research is warranted to elucidate the precise mechanisms and explore potential therapeutic interventions based on these genetic findings.

Altered pharmacology and toxicology during ageing: implications for lung disease.

PURPOSE OF REVIEW: Drug use in elderly people is high compared to younger people. Simultaneously, elderly are at greater risk when exposed to environmental substances. It is puzzling therefore, that ageing, as a variable in pharmacological and toxicological processes is not investigated in more depth. Moreover, recent data suggest that molecular manifestations of the ageing process also hallmark the pathogenesis of chronic lung diseases, which may impact pharmacology and toxicology. RECENT FINDINGS: In particular, absorption, distribution, metabolism and excretion (ADME) processes of drugs and toxins alter because of ageing. Polypharmacy, which is quite usual with increasing age, increases the risk of drug-drug interactions. Individual differences in combination of drugs use in conjunction with individual variations in drug metabolizing enzymes can influence lung function. SUMMARY: Exploring exposure throughout life (i.e. during ageing) to potential triggers, including polypharmacy, may avoid lung disease or unexplained cases of lung damage. Understanding of the ageing process further unravels critical features of chronic lung disease and helps to define new protective targets and therapies. Optimizing resilience can be key in pharmacology and toxicology and helps in maintaining healthy lungs for a longer period.

Senescence in pulmonary arterial hypertension: is there a link?

PURPOSE OF REVIEW: Cellular senescence has been recognized as a promising target in the treatment of many cardiovascular diseases. The pathways involved in the development of senescence share many similarities with pathobiological mechanisms of pulmonary arterial hypertension (PAH). But the potential of senolytics to improve pulmonary hemodynamics and to reduce vascular remodelling in PAH has thus far not been investigated in depth. RECENT FINDINGS: PAH does not seem to be a disease of only young people since the mean age of PAH patients is constantly increasing. Changes in expression of senescence biomarkers related to cell cycle arrest, namely upregulation of the tumour suppressor protein p53 and the cell cycle inhibitors p16ink4A an p21cip1 as well as an increase in apoptosis resistance biomarker Bcl2 (B-cell lymphoma 2) and development of senescence-associated phenotype characterized by excessive production of matrix metalloproteinase 2 and interleukin 6 were demonstrated in PAH patients. Initiatives to link the senescence-modulating effect of certain compounds to clinically relevant outcomes in PAH are still limited. SUMMARY: Further exploration of the role of senescence in the pathobiology of PAH may point to new relevant treatment strategies. Identification of the cell-specific senescence biomarkers which can be used in vivo, could further promote identification of clinically relevant pathways and design of clinical studies which will help to establish effective therapeutic use of senolytic compounds.

Drug-induced comorbidities in patients with sarcoidosis.

PURPOSE OF REVIEW: Sarcoidosis is a chronic multisystemic inflammatory disease of unknown aetiology with a wide range of highly variable clinical manifestations and unpredictable disease course. Sarcoidosis patients may present with specific organ-related symptoms involving functional impairments, and less specific symptoms. The decision whether and when to treat a sarcoidosis patient with pharmacotherapy depends on two major factors: risk of organ failure and/or death and impairment of quality of life. This decision is complex and not standardized. RECENT FINDINGS: Glucocorticoids (GCs) are recommended as initial treatment, when needed. Subsequent GC-sparing alternatives frequently follow. Comorbidities or adverse drug reactions (ADRs) from drugs used in sarcoidosis treatment are sometimes very hard to differentiate from symptoms associated with the disease itself, which may cause diagnostic dilemmas. An ideal approach to minimalize ADRs would involve genetic screening prior to prescribing certain 'high-risk drugs' and therapeutic drug monitoring during treatment. Pharmacogenomic testing aims to guide appropriate selection of medicines, with the potential of reducing unnecessary polypharmacy while improving clinical outcomes. SUMMARY: A multidisciplinary approach to the management of sarcoidosis may avoid unnecessary ADRs. It is important to consider the possibility of drug-induced damage in sarcoidosis, especially if the clinical situation deteriorates after the introduction of a particular drug.

Pulmonary toxicity associated with occupational and environmental exposure to pesticides and herbicides.

PURPOSE OF REVIEW: Critical review on the notion that exposure to pesticides and herbicides lead to adverse effects in pulmonary health. RECENT FINDINGS: The lung effects of several chemical classes of pesticides and herbicides is biologically plausible. However, the studies that describe the association between exposure and toxic lung effects have numerous limitations. Critical evaluation of the studies that are performed shows that assessment of occupational or environmental exposure to pesticides and herbicides is cumbersome. Moreover, the health effects are not always clearly established due to the use of questionnaires and self-reported data instead of lung function measurements or diagnostic work-up by physicians.Future studies should preferably better characterize the exposure. Genetic phenotyping should be included to understand and strengthen possible (individual) associations between exposure and health outcome. It should be realized that combined exposure to multiple environmental chemicals may lead to different health effects than exposure to individual chemicals. SUMMARY: The relation between exposure to pesticides and herbicides and lung toxicity is less clear than generally assumed. Adverse lung effects seem multifactorial and needs further research. Preventive measures remain key.

Effect of oral or intragastric delivery of the bitter tastant quinine on food intake and appetite sensations: a randomised crossover trial.

Stimulation of gastrointestinal taste receptors affects eating behaviour. Intraduodenal infusion of tastants leads to increased satiation and reduced food intake, whereas intraileal infusion of tastants does not affect eating behaviour. Currently, it is unknown whether oral- or intragastric administration of tastants induces a larger effect on eating behaviour. This study investigated the effects of oral- and/or intragastric administration of quinine on food intake, appetite sensations and heart rate variability (HRV). In a blinded randomised crossover trial, thirty-two healthy volunteers participated in four interventions with a 1-week washout: oral placebo and intragastric placebo (OPGP), oral quinine and intragastric placebo (OQGP), oral placebo and intragastric quinine (OPGQ) and oral quinine and intragastric quinine (OQGQ). On test days, 150 min after a standardised breakfast, subjects ingested a capsule containing quinine or placebo and were sham-fed a mixture of quinine or placebo orally. At 50 min after intervention, subjects received an ad libitum meal to measure food intake. Visual analogue scales for appetite sensations were collected, and HRV measurements were performed at regular intervals. Oral and/or intragastric delivery of the bitter tastant quinine did not affect food intake (OPGP: 3273·6 (sem 131·8) kJ, OQGP: 3072·7 (sem 132·2) kJ, OPGQ: 3289·0 (sem 132·6) kJ and OQGQ: 3204·1 (sem 133·1) kJ, P = 0·069). Desire to eat and hunger decreased after OQGP and OPGQ compared with OPGP (P < 0·001 and P < 0·05, respectively), whereas satiation, fullness and HRV did not differ between interventions. In conclusion, sole oral sham feeding with and sole intragastric delivery of quinine decreased desire to eat and hunger, without affecting food intake, satiation, fullness or HRV.

Effects of gastrointestinal delivery of non-caloric tastants on energy intake: a systematic review and meta-analysis.

PURPOSE: Taste receptors are expressed throughout the gastrointestinal tract. The activation of post-oral taste receptors using tastants could provide a non-invasive treatment option in combating the obesity epidemic. The aim of this review was to examine the effect of post-oral delivery of non-caloric tastants on eating behavior reflected by primary outcome energy intake and secondary outcomes GI symptoms and perceptions and potential underlying mechanisms. This review was conducted according to the PRISMA guidelines for systematic reviews. METHODS: A systematic literature search of the Cochrane, PubMed, Embase, and Medline databases was performed. This systematic review and meta-analysis was registered in the PROSPERO database on 26 February 2020 (ID: CRD42020171182). Two researchers independently screened 11,912 articles and extracted information from 19 articles. If at least two studies investigated the effect of the same taste compound on primary outcome energy intake, a meta-analysis was performed to determine pooled effect sizes. RESULTS: Nineteen papers including healthy volunteers were included. In the 19 papers analyzed, effects of various tastants were investigated in healthy volunteers. Most extensively investigated were bitter tastants. The meta-analysis of effects of bitter tastants showed a significant reduction in energy intake of 54.62 kcal (95% CI - 78.54 to - 30.69, p = 0.0014). CONCLUSIONS: Bitter stimuli are most potent to influence eating behavior. Energy intake decreased after post-oral delivery of bitter tastants. This highlights the potential of a preventive role of bitter tastants in battling the obesity epidemic.

Sensory-specific satiety, the variety effect and physical context: Does change of context during a meal enhance food intake?

Food variety has been shown to increase food intake, and sensory-specific satiety (a relative decrease in pleasantness of a food as it is consumed) has been proposed as the mechanism through which variety increases consumption. The aim of this study was to investigate whether variation of eating context can add to experienced meal variety and hence increase consumption even further. A total of 128 participants were assigned to one of four conditions in which they first ate a specific food item (ad libitum) until satiated, after which they consumed a second course ad libitum of either the same or a different food in either the same context or in a different context. We hypothesized that, compared to eating the same food in the same context during the second course, introducing a different food item or changing the context for the second course increases consumption (of the second course), and changing both food and context enhances food intake to a greater degree than only changing the food or changing the context. Results indicated that food variety (introducing a different food) significantly increased consumption in the second course, but that a context switch did not enhance consumption. These results suggest that there is little reason to believe that sensory-specific satiety is context specific.

How does scientific information reach the consumer? A case study among students into providing verbal information on dietary supplements at point of purchase.

Consumers of dietary supplements should be made aware of the benefits and risks of these products. This case study therefore aimed to identify the content of the risk-benefit information provided during the purchase of St. John's wort supplements and how consumers perceive this information. Fifteen participants visited a shop to purchase St. John's wort supplements after which they were interviewed on the provided information during the visit. This case study shows that the spontaneous information provision is not consistent in Dutch drugstores and health food shops. The provided information was either very detailed, or no information was given at all. The perceived reliability of information was mainly determined by the authority of the employee and the type of shop where the product was purchased. Information consistency at the moment of purchase is of influence in the perceived value of it.

Interaction of diet and drugs in lung disease.

PURPOSE OF REVIEW: The current review aims to seek attention for the interaction between drugs and nutrition. Traditionally, drugs and nutrition are regarded as separate categories. Nutrition is to maintain health and drugs are for curing disease. Dieticians deal with food and the medical doctor prescribes drugs. During the last decade, both categories are getting closer. RECENT FINDINGS: Some drugs used in pulmonology lead to decrease in nutrients. Other drugs negatively affect taste. This is remarkable because the diseases for which these drugs are intended, benefit from nutrition. Gradually examples emerge that suggest that the action of drugs profit from certain dietary components. SUMMARY: A closer look into the interaction between diet and drugs will eventually benefit the patient.

Role of antioxidants in the treatment of gastroesophageal reflux disease-associated idiopathic pulmonary fibrosis.

PURPOSE OF REVIEW: Idiopathic pulmonary fibrosis (IPF) is a terminal lung disease of largely unknown cause. Gastroesophageal reflux disease (GERD) was recently discovered to be a trigger for the development of IPF. The current pharmaceutical approach to IPF falls short and there is a pressing need for improved therapeutic options. The present review describes the currently available knowledge regarding the role of oxidative stress and inflammation in the pathophysiology of IPF and GERD and determines the potential use of antioxidants as a treatment option for GERD-associated IPF. RECENT FINDINGS: IPF and GERD share a similar pathophysiology, as oxidative stress and inflammation play a pivotal role in both conditions. This raises the question whether antioxidant treatment could be a well-tolerated and effective means to alleviate at least some of the symptoms of both conditions. In IPF, antioxidant supplementation complements the inadequately working antioxidant defense system of the lung, reducing oxidative stress and inflammation. In GERD, antioxidants increase levels of endogenous antioxidants, decrease pepsin and gastric acid production, lipid peroxidation, and ulceration, and alleviate subsequent damage to the gastric mucosa. SUMMARY: The increased comorbidity of GERD in IPF patients makes it clear that there is a connection between GERD and IPF. As current treatment options are still inadequate to improve the condition and increase the survival rate of IPF patients, alternative treatment options are crucial. Based on the reviewed scientific evidence, antioxidant supplementation could complement standard IPF treatment, certainly in GERD-associated IPF.

Protective role of c-Jun N-terminal kinase-2 (JNK2) in ibuprofen-induced acute liver injury.

Ibuprofen is a worldwide used non-steroidal anti-inflammatory drug which may cause acute liver injury (ALI) requiring liver transplantation. We aimed to unveil the molecular pathways involved in triggering ibuprofen-induced ALI, which, at present, remain elusive. First, we investigated activation of essential pathways in human liver sections of ibuprofen-induced ALI. Next, we assessed the cytotoxicity of ibuprofen in vitro and developed a novel murine model of ibuprofen intoxication. To assess the role of JNK, we used animals carrying constitutive deletion of c-Jun N-terminal kinase 1 (Jnk1-/- ) or Jnk2 (Jnk2-/- ) expression and included investigations using animals with hepatocyte-specific Jnk deletion either genetically (Jnk1Δhepa ) or by siRNA (siJnk2Δhepa ). We found in human and murine samples of ibuprofen-induced acute liver failure that JNK phosphorylation was increased in the cytoplasm of hepatocytes and other non-liver parenchymal cells (non-LPCs) compared with healthy tissue. In mice, ibuprofen intoxication resulted in a significantly stronger degree of liver injury compared with vehicle-treated controls as evidenced by serum transaminases, and hepatic histopathology. Next, we investigated molecular pathways. PKCα, AKT, JNK and RIPK1 were significantly increased 8 h after ibuprofen intoxication. Constitutive Jnk1-/- and Jnk2-/- deficient mice exhibited increased liver dysfunction compared to wild-type (WT) animals. Furthermore, siJnk2Δhepa animals showed a dramatic increase in biochemical markers of liver function, which correlated with significantly higher serum liver enzymes and worsened liver histology, and MAPK activation compared to Jnk1Δhepa or WT animals. In our study, cytoplasmic JNK activation in hepatocytes and other non-LPCs is a hallmark of human and murine ibuprofen-induced ALI. Functional in vivo analysis demonstrated a protective role of hepatocyte-specific Jnk2 during ibuprofen ALI. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Non-steroidal anti-inflammatory drugs increase urinary neutrophil gelatinase-associated lipocalin in recreational runners.

OBJECTIVES: To study the effects of running with/without the use of pain killers on urinary neutrophil gelatinase-associated lipocalin (uNGAL) and other parameters of kidney function in recreational runners. METHODS: Participants of the 10- and 21.1-km Weir Venloop race were enrolled and their urine samples collected before and after the run. Urine dipstick and other conventional tests used to assess kidney function were performed. The presence of ibuprofen, diclofenac, naproxen, and/or paracetamol was assessed by LC-MS/MS. uNGAL was measured with a two-step chemiluminescent immunoassay. RESULTS: NSAIDs/analgesics were detected in urine of 5 (14.4%) 10-km runners and 13 (28.9%) 21.1-km runners. Only half-marathon participants showed significant increases in uNGAL (pre: 11.7 [7.1-34.3] ng/mL; post: 33.4 [17.4-50.4] ng/mL; P = .0038). There was a significant effect of NSAID/analgesic use on uNGAL increase (F2, 76  = 4.210, P = .004). Post hoc tests revealed that uNGAL increased significantly in runners who tested positive for ibuprofen/naproxen compared to runners who did not use any medications (P = .045) or those who tested positive for paracetamol (P = .033). Running distance had a significant influence on the increase in uNGAL (F1, 53  = 4.741, P < .05), specific gravity (F1, 60  = 9.231, P < .01), urinary creatinine (F1, 61  = 10.574, P < .01), albumin (F1, 59  = 4.888, P < .05), and development of hematuria (χ2 (4) = 18.44, P = .001). CONCLUSIONS: Running distance and use of ibuprofen/naproxen were identified as risk factors for uNGAL increase in recreational runners.

The dietary antioxidant quercetin reduces hallmarks of bleomycin-induced lung fibrogenesis in mice.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, lethal disease of which the etiology is still not fully understood. Current treatment comprises two FDA-approved drugs that can slow down yet not stop or reverse the disease. As IPF pathology is associated with an altered redox balance, adding a redox modulating component to current therapy might exert beneficial effects. Quercetin is a dietary antioxidant with strong redox modulating capacities that is suggested to exert part of its antioxidative effects via activation of the redox-sensitive transcription factor Nrf2 that regulates endogenous antioxidant levels. Therefore, the aim of the present study was to investigate if the dietary antioxidant quercetin can exert anti-fibrotic effects in a mouse model of bleomycin-induced pulmonary fibrogenesis through Nrf2-dependent restoration of redox imbalance. METHODS: Homozygous Nrf2 deficient mice and their wildtype littermates were fed a control diet without or with 800 mg quercetin per kg diet from 7 days prior to a single 1 µg/2 µl per g BW bleomycin challenge until they were sacrificed 14 days afterwards. Lung tissue and plasma were collected to determine markers of fibrosis (expression of extracellular matrix genes and histopathology), inflammation (pulmonary gene expression and plasma levels of tumor necrosis factor-α (TNFα) and keratinocyte chemoattrachtant (KC)), and redox balance (pulmonary gene expression of antioxidants and malondialdehyde-dG (MDA)- DNA adducts). RESULTS: Mice fed the enriched diet for 7 days prior to the bleomycin challenge had significantly enhanced plasma and pulmonary quercetin levels (11.08 ± 0.73 µM versus 7.05 ± 0.2 µM) combined with increased expression of Nrf2 and Nrf2-responsive genes compared to mice fed the control diet in lung tissue. Upon bleomycin treatment, quercetin-fed mice displayed reduced expression of collagen (COL1A2) and fibronectin (FN1) and a tendency of reduced inflammatory lesions (2.8 ± 0.7 versus 1.9 ± 0.8). These beneficial effects were accompanied by reduced pulmonary gene expression of TNFα and KC, but not their plasma levels, and enhanced Nrf2-induced pulmonary antioxidant defences. In Nrf2 deficient mice, no effect of the dietary antioxidant on either histology or inflammatory lesions was observed. CONCLUSION: Quercetin exerts anti-fibrogenic and anti-inflammatory effects on bleomycin-induced pulmonary damage in mice possibly through modulation of the redox balance by inducing Nrf2. However, quercetin could not rescue the bleomycin-induced pulmonary damage indicating that quercetin alone cannot ameliorate the progression of IPF.

Analysis and reflection on the role of the 90-day oral toxicity study in European chemical risk assessment.

The 90-day toxicity study is one of the studies used in the safety assessment of food ingredients, medicines or other chemical substances. This paper reviews the current role of the 90-day oral toxicity study in European regulatory dossiers of chemicals by reviewing EU legislation and EU and OECD guidance documents. Regulatory provisions with regard to necessity, objectives and design of such 90-day toxicity studies vary between the different sectors addressed in this review. Most often the 90-day study is expected to be part of the standard test battery used for chemical risk assessment, without necessarily being a legal requirement and its objectives may vary between regulatory domains. Exceptions, when a 90-day study is not required are spelled out in the chemicals legislation and for food contact materials. The sectorial study design requirements of the 90-day toxicity study are very often embedded in the OECD TG 408 protocol. Differences in study objectives are not necessarily reflected in specific study designs. Considering the call for the reduction of using experimental animals for scientific purposes and the fact that a 90-day study may serve different purposes, consistency between the necessity to conduct such a study, its objectives and the study design to achieve these objectives may improve judicious use of laboratory animals. Thus there may be an opportunity to reflect and further optimise the design of in vivo toxicology studies, such as the 90-day study. This should be based on a systematic analysis of past studies and risk assessments.

The Molecular Mechanisms of Adaptive Response Related to Environmental Stress.

The exposure of living organisms to environmental stress triggers defensive responses resulting in the activation of protective processes. Whenever the exposure occurs at low doses, defensive effects overwhelm the adverse effects of the exposure; this adaptive situation is referred to as "hormesis". Environmental, physical, and nutritional hormetins lead to the stimulation and strengthening of the maintenance and repair systems in cells and tissues. Exercise, heat, and irradiation are examples of physical hormetins, which activate heat shock-, DNA repair-, and anti-oxidative-stress responses. The health promoting effect of many bio-actives in fruits and vegetables can be seen as the effect of mildly toxic compounds triggering this adaptive stimulus. Numerous studies indicate that living organisms possess the ability to adapt to adverse environmental conditions, as exemplified by the fact that DNA damage and gene expression profiling in populations living in the environment with high levels of air pollution do not correspond to the concentrations of pollutants. The molecular mechanisms of the hormetic response include modulation of (a) transcription factor Nrf2 activating the synthesis of glutathione and the subsequent protection of the cell; (b) DNA methylation; and (c) microRNA. These findings provide evidence that hormesis is a toxicological event, occurring at low exposure doses to environmental stressors, having the benefit for the maintenance of a healthy status.

Tamsulosin Associated with Interstitial Lung Damage in CYP2D6 Variant Alleles Carriers.

Drugs are serious but underestimated causative agents of interstitial lung disease (ILD). Both cytotoxic and immune mechanisms may be involved in drug-induced ILD (DI-ILD). We aimed to investigate whether polymorphisms of relevant CYP enzymes involved in the metabolization of tamsulosin might explain the pathologic mechanism of the DI-ILD in the cases with suspected tamsulosin DI-ILD. We collected 22 tamsulosin-associated DI-ILD cases at two ILD Expertise Centers in the Netherlands between 2009 and 2020. CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 single nucleotide polymorphisms were genotyped and compared with a control group of 78 healthy Caucasian male volunteers. Nine cases were phenotyped as CYP2D6 poor metabolizers and 13 as CYP2D6 intermediate metabolizers. The phenotypes of the cases differed significantly from those of the healthy controls, with more poor metabolizers. After withdrawal of tamsulosin, the pulmonary condition of three cases had improved, six patients had stabilized, and one patient stabilized after reducing the tamsulosin dose. The described 22 cases suggest that an association between the presence of CYP2D6 allelic variants and tamsulosin-associated ILD is highly likely. These cases highlight the importance of both clinical and genetic risk stratification aimed to achieve a more accurate prevention of DI-ILD in the future and enhance the quality of life of patients.

The Role of Circulating Lycopene in Low-Grade Chronic Inflammation: A Systematic Review of the Literature.

BACKGROUND AND AIMS: In recent years, it has become clear that low-grade chronic inflammation is involved in the onset and progression of many non-communicable diseases. Many studies have investigated the association between inflammation and lycopene, however, results have been inconsistent. This systematic review aims to determine the impact of circulating lycopene on inflammation and to investigate the effect of consuming tomato products and/or lycopene supplements on markers of inflammation. METHODS: Eligible studies, published before March 2020, were identified from PubMed, EBSCOhost and ScienceDirect. Human studies published in English, that evaluated the effect of circulating lycopene in relation to inflammation biomarkers were screened and included. Studies assessing lycopene intake or general intake of carotenoids/antioxidants without measuring circulating lycopene, as well as those not reporting inflammation biomarkers as outcomes, were excluded. RESULTS: Out of 80 publications identified and screened, 35 met the inclusion criteria. Results from 18 cross-sectional studies suggest that lycopene levels are adversely affected during inflammation and homeostatic imbalance. Most of the 17 included intervention studies reported increased circulating lycopene levels after tomato/lycopene supplementation, but almost no changes in inflammation biomarkers were observed. CONCLUSIONS: There is little evidence that increasing tomato intake or lycopene supplementation diminuates this inflammation. However, depletion of lycopene may be one of the first signs of low-grade inflammation. The available data thereby imply that it is beneficial to consume lycopene-rich foods occasionally to stay healthy and keep circulating lycopene at a basal level.

Drug-induced interstitial lung disease: role of pharmacogenetics in predicting cytotoxic mechanisms and risks of side effects.

PURPOSE OF REVIEW: The diagnosis of drug-induced interstitial lung disease (DI-ILD) is challenging and mainly made by exclusion of other possible causes. Toxicity can occur as a cause of drug(s) or drug-drug interactions. In this review, we summarize the possible role of pharmacogenetics of metabolizing enzymes in DI-ILD. RECENT FINDINGS: Knowledge of the genetic predispositions of enzymes involved in drug metabolization and their relation with proposed cytotoxic mechanisms of DI-ILD, in particular direct cell toxicity and free oxygen radical production is increasing. The cytochrome P450 enzyme family and other enzymes play an important role in the metabolism of all sorts of ingested, injected, or inhaled xenobiotic substances. The liver is the major site for metabolism. Metabolic cytotoxic mechanisms have however also been detected in lung tissue. Polymorphisms in genes coding for enzymes that influence metabolic activity may lead to localized (toxic) reactions and tissue damage. This knowledge may be helpful in preventing the risk of DI-ILD. SUMMARY: Drug toxicity can be the consequence of absence or very poor enzyme activity, especially if no other metabolic route is available. In the case of reduced enzyme activity, it is recommended to reduce the dose or to prescribe an alternative drug, which is metabolized by a different, unaffected enzyme system to prevent toxic side effects. However, enhanced enzyme activity may lead to excessive formation of toxic and sometimes reactive metabolites. Therefore, knowing a patient's drug-metabolizing profile before drug prescription is a promising way to prevent or explain DI-ILD.