Longitudinal effects of a common UMOD variant on kidney function, blood pressure, cognitive and physical function in older women and men.

Genetic variants in UMOD associate with kidney function and hypertension. These phenotypes are also linked to sex-related differences and impairment in cognitive and physical function in older age. Here we evaluate longitudinal associations between a common UMOD rs4293393-A>G variant and changes in estimated glomerular filtration rate (eGFR), blood pressure (BP), cognitive and physical function parameters in older participants in the BASE-II after long-term follow-up as part of the GendAge study. Overall, 1010 older participants (mean age 75.7 ± 3.7 years, 51.6% women) were analyzed after follow-up (mean 7.4 years) both in cross-sectional analysis and in longitudinal analysis as compared to baseline. In cross-sectional analysis, heterozygous G-allele carriers exhibited significantly higher eGFR values (AA, 71.3 ml/min/1.73 m2, 95% CI, 70.3-72.3 vs. AG, 73.5 ml/min/1.73 m2, 95% CI, 72.1-74.9, P = 0.033). Male heterozygous G-allele carriers had lower odds of eGFR < 60 mL/min/1.73 m2 (OR 0.51, 95% CI, 0.28-0.95, P = 0.032) and in Timed Up and Go-Test ≥ 10 s (OR 0.50, 95% CI, 0.29-0.85, P = 0.011) whereas women were less likely to have hypertension (OR 0.58, CI, 0.37-0.91, P = 0.018). UMOD genotypes were not significantly associated with longitudinal changes in any investigated phenotype. Thus, while the impact of UMOD rs4293393 on kidney function is maintained in aging individuals, this variant has overall no impact on longitudinal changes in BP, kidney, cognitive or functional phenotypes. However, our results suggest a possible sex-specific modifying effect of UMOD on eGFR and physical function in men and hypertension prevalence in women.

Effect of a common UMOD variant on kidney function, blood pressure, cognitive and physical function in a community-based cohort of older adults.

In genome-wide association studies, genetic variants in the UMOD gene associate with kidney function, blood pressure (BP), and hypertension. Elevated BP is linked to kidney function and impaired cognitive as well as physical performance in later life. We investigated the association between UMOD rs4293393-A > G and kidney function, BP, cognitive and physical function in the Berlin Aging Study II (BASE-II). Data of 1556 older BASE-II participants (mean age 68.2 ± 3.7 years) were analyzed. BP was determined by standardized automated measurements, estimated glomerular filtration rate (eGFR) by CKD Epidemiology Collaboration creatinine equation. Cognitive function was assessed by Mini-Mental State Examination and Digit Symbol Substitution Test, while physical function by Handgrip Strength and Timed Up and Go-Test. Association analyses were performed by covariance and logistic regression models adjusting for sex. G-allele carriers at UMOD rs4293393 exhibited significantly higher eGFR values compared to non-carriers (AA, 76.4 ml/min/1.73 m², CI: 75.7-77.2 vs. AG, 78.4 ml/min/1.73 m², CI: 77.3-79.5 vs. GG, 78.5 ml/min/1.73 m², CI: 75.4-81.7; P = 0.010), and a lower risk of eGFR < 60 mL/min/1.73 m2 (AG, OR: 0.63, CI: 0.41-0.97, P = 0.033). However, UMOD rs4293393 genotypes were not associated with BP, diagnosis of hypertension or cognitive and physical function parameters. Our data corroborate previous findings on the association of UMOD rs4293393-G with better kidney function in older adults. However, no association between UMOD and BP or physical and cognitive parameters in these community-dwelling older adults was detected.

Reviewing the effects of thiazide and thiazide-like diuretics as photosensitizing drugs on the risk of skin cancer.

BACKGROUND: Thiazide diuretics and particularly hydrochlorothiazide were recently linked to an increased risk of skin cancer, which was attributed to the photosensitizing properties of these drugs. Given the widespread use of thiazide diuretics, a potential skin cancer promoting effect would impose an important public health concern. OBJECTIVE: To critically appraise in a narrative review, the association between use of thiazide and thiazide-like diuretics and risk of skin cancer. METHODS: We evaluated chemical structures and photosensitizing potential of selected thiazide and thiazide-like diuretics. Moreover, we searched PubMed up to December 2018 for observational studies assessing the association between use of thiazide or thiazide-like diuretics and risk of skin cancer. Study quality was assessed for major methodological biases. RESULTS: Commonly used thiazide and thiazide-like diuretics carry resonating structural components, such as sulfonamide groups that contribute to their photosensitizing activity. Overall, 13 observational (9 case-control, 4 cohort) studies assessed the association between use of different thiazide or thiazide-like diuretics and risk of several skin cancer types. Of those, nine studies showed positive associations ranging from 3% increased risk for bendroflumethiazide and basal cell carcinoma to 311% increased risk for thiazide diuretics and squamous cell carcinoma. All studies had important design-related methodological limitations including potential confounding by indication, detection bias, and time-window bias. CONCLUSION: Commonly used thiazide and thiazide-like diuretics have photosensitizing potential, and some observational studies with important methodological limitations have linked their use to an increased risk of skin cancer. Well designed observational studies are needed to provide more solid evidence on this possible association.

Importance of in vitro conditions for modeling the in vivo dose in humans by in vitro-in vivo extrapolation (IVIVE).

In vitro studies are increasingly proposed to replace in vivo toxicity testing of substances. We set out to apply physiologically based pharmacokinetic (PBPK) modeling to predict the in vivo dose of amiodarone that leads to the same concentration-time profile in the supernatant and the cell lysate of cultured primary human hepatic cells (PHH). A PBPK human model was constructed based on the structure and tissue distribution of amiodarone in a rat model and using physiological human parameters. The predicted concentration-time profile in plasma was in agreement with human experimental data with the unbound fraction of amiodarone in plasma crucially affecting the goodness-of-fit. Using the validated kinetic model, we subsequently described the in vitro concentration-time data of amiodarone in PHH culture. However, this could be only appropriately modeled under conditions of zero protein binding and the very low clearance of the in vitro system in PHH culture. However, these represent unphysiological conditions and, thus, the main difference between the in vivo and the in vitro systems. Our results reveal that, for meaningful quantitative extrapolation from in vitro to in vivo conditions in PBPK studies, it is essential to avoid non-intended differences between these conditions. Specifically, clearance and protein binding, as demonstrated in our analysis of amiodarone modeling, are important parameters to consider.

Small molecules as therapy for uveitis: a selected perspective of new and developing agents.

INTRODUCTION: Intraocular inflammation (uveitis) remains a significant burden of legal blindness. Because of its immune mediated and chronic recurrent nature, common therapy includes corticosteroids, disease-modifying anti-rheumatic drugs and more recently biologics as immune modulatory agents. The purpose of this article is to identify the role of new treatment approaches focusing on small molecules as therapeutic option in uveitis. Areas covered: A MEDLINE database search was conducted through February 2017 using the terms 'uveitis' and 'small molecule'. To provide ongoing and future perspectives in treatment options, also clinical trials as registered at ClinicalTrials.gov were included. Both, results from experimental as well as clinical research in this field were included. Since this field is rapidly evolving, a selection of promising agents had to be made. Expert opinion: Small molecules may interfere at different steps of the inflammatory cascade and appear as an interesting option in the treatment algorithm of uveitis. Because of their highly targeted molecular effects and their favorable bioavailability with the potential of topical application small molecules hold great promise. Nevertheless, a careful evaluation of these agents has to be made, since current experience is almost exclusively based on experimental uveitis models and few registered trials.

Statin intolerance - a question of definition.

INTRODUCTION: Statin therapy is the backbone of pharmacologic therapy for low-density lipoproteins cholesterol lowering and plays a pivotal role in cardiovascular disease prevention. Statin intolerance is understood as the inability to continue using a statin to reduce individual cardiovascular risk sufficiently, due to the development of symptoms or laboratory abnormalities attributable to the initiation or dose escalation of a statin. Muscle symptoms are the most common side effects observed. Areas covered: The main aim of this article is to present a review on published definitions of statin intolerance. In addition, a brief review on clinical aspects and risk factors of statin intolerance is provided and features for a common definition for statin intolerance are suggested. Expert opinion: A definition of statin intolerance by major drug regulatory agencies is not available. In clinical studies, different definitions are chosen and results are not comparable; different medical associations do not agree on one common definition. There is an unmet need to establish a common definition of statin intolerance to ensure an appropriate clinical use of this important drug class. Further work is required to develop a consensus definition on statin intolerance that could have significant positive impact on both research and clinical management.