Rewiring of liver diurnal transcriptome rhythms by triiodothyronine (T3) supplementation.

Diurnal (i.e., 24 hr) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (T3) state was induced in mice by supplementing T3 in the drinking water, which affected body temperature, and oxygen consumption in a time-of-day-dependent manner. A 24-hr transcriptome profiling of liver tissue identified 37 robustly and time independently T3-associated transcripts as potential TH state markers in the liver. Such genes participated in xenobiotic transport, lipid and xenobiotic metabolism. We also identified 10-15% of the liver transcriptome as rhythmic in control and T3 groups, but only 4% of the liver transcriptome (1033 genes) were rhythmic across both conditions - amongst these, several core clock genes. In-depth rhythm analyses showed that most changes in transcript rhythms were related to mesor (50%), followed by amplitude (10%), and phase (10%). Gene set enrichment analysis revealed TH state-dependent reorganization of metabolic processes such as lipid and glucose metabolism. At high T3 levels, we observed weakening or loss of rhythmicity for transcripts associated with glucose and fatty acid metabolism, suggesting increased hepatic energy turnover. In summary, we provide evidence that tonic changes in T3 levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.

Many environmental conditions, including light and temperature, vary with a daily rhythm that affects how animals interact with their surroundings. Indeed, most species have developed so-called circadian clocks: internal molecular timers that cycle approximately every 24 hours and regulate many bodily functions, including digestion, energy metabolism and sleep. The energy metabolism of the liver ­ the chemical reactions that occur in the organ to produce energy from nutrients ­ is controlled both by the circadian clock system, and by the hormones produced by a gland in the neck called the thyroid. However, the interaction between these two regulators is poorly understood. To address this question, de Assis, Harder et al. elevated the levels of thyroid hormones in mice by adding these hormones to their drinking water. Studying these mice showed that, although thyroid hormone levels were good indicators of how much energy mice burn in a day, they do not reflect daily fluctuations in metabolic rate faithfully. Additionally, de Assis, Harder et al. showed that elevating T₃, the active form of thyroid hormone, led to a rewiring of the daily rhythms at which genes were turned on and off in the liver, affecting the daily timing of processes including fat and cholesterol metabolism. This occurred without changing the circadian clock of the liver directly. De Assis, Harder et al.'s results indicate that time-of-day critically affects the action of thyroid hormones in the liver. This suggests that patients with hypothyroidism, who produce low levels of thyroid hormones, may benefit from considering time-of-day as a factor in disease diagnosis, therapy and, potentially, prevention. Further data on the rhythmic regulation of thyroid action in humans, including in patients with hypothyroidism, are needed to further develop this approach.

High-dose spironolactone lacks effectiveness in treatment of fibromyalgia (RCT).

BACKGROUND: Spironolactone (SPL) is a reversible mineralocorticoid receptor (MR) and androgen receptor (AR) antagonist which attracts pharmacotherapeutic interest not only because of its beneficial effects in heart failure but also because of the pathogenetic roles of MR and AR activities in neuropsychiatric diseases. Recently, beneficial and rapid-onset effects of SPL have been documented in a case series of women with fibromyalgia syndrome (FMS). To reaffirm this observation, we performed a double-blind placebo-controlled randomized clinical trial (RCT). METHODS: A total of 69 patients were screened, 56 patients were eligible and randomized to SPL or placebo (each n = 28). Forty-three patients completed the clinical trial to the last visit (n = 21 and n = 22). After a run-in phase of 50 and 100 mg/day, 200 mg/day SPL or placebo were applied between days 7 and 28. Primary outcome was the change in the FIQ-G score (Fibromyalgia Impact Questionnaire, German version). Secondary outcome parameters were the changes in pain (numeric rating scale, NRS), mood (ADS), quality of life (SF-36) and change in FIQ scores 14 days after the end of the medication. RESULTS: SPL of 200 mg/day did not change significantly either the primary or the secondary end points. SPL evoked a transient rise in serum potassium and a transient fall in GFR maximal after 2 weeks, but without clinical relevance. CONCLUSIONS: SPL at 200 mg/day does not improve symptoms in women with FMS, but was considered not to cause harm. SIGNIFICANCE: The mineralocorticoid receptor and androgen receptor antagonist spironolactone is repeatedly tested for its therapeutic effectivity against neuropsychiatric disorders. The present RCT demonstrated that 200 mg spironolactone does not change the symptoms of the fibromyalgia syndrome (FMS) in adult women. Between 2 and 4 weeks, spironolactone evokes a transient decrease in GFR and increase in serum potassium. Spironolactone cannot be recommended for the treatment of FMS.

Interaction of Phytocompounds of Echinacea purpurea with ABCB1 and ABCG2 Efflux Transporters.

Preparations of Echinacea purpurea (E. purpurea) are widely used for the management of upper respiratory infections, influenza, and common cold, often in combination with other conventional drugs. However, the potential of phytochemical constituents of E. purpurea to cause herb-drug interactions via ABCB1 and ABCG2 efflux transporters remains elusive. The purpose of this study was to investigate the impact of E. purpurea-derived caffeic acid derivatives (cichoric acid and echinacoside) and tetraenes on the mRNA and protein expression levels as well as on transport activity of ABCB1 and ABCG2 in intestinal (Caco-2) and liver (HepG2) cell line models. The safety of these compounds was investigated by estimating EC20 values of cell viability assays in both cell lines. Regulation of ABCB1 and ABCG2 protein in these cell lines were analyzed after 24 h exposure to the compounds at 1, 10, and 50 µg/mL. Bidirectional transport of 0.5 µg/mL Hoechst 33342 and 5 µM rhodamine across Caco-2 monolayer and profiling for intracellular concentrations of the fluorophores in both cell lines were conducted to ascertain inhibition effects of the compounds. Cichoric acid showed no cytotoxic effect, while the EC20 values of tetraenes and echinacoside were 45.0 ± 3.0 and 52.0 ± 4.0 µg/mL in Caco-2 cells and 28.0 ± 4.3 and 62.0 ± 9.9 µg/mL in HepG2 cells, respectively. In general, the compounds showed heterogeneous induction of ABCB1 with the strongest 3.6 ± 1.2-fold increase observed for 10 µg/mL tetraenes in Caco-2 cells (p < 0.001). However, the compounds did not induce ABCG2. None of the phytocompounds inhibited significantly net flux of the fluorophores across Caco-2 monolayers. Overall, tetraenes moderately induced ABCB1 but not ABCG2 in Caco-2 and HepG2 cells while no compound significantly inhibited activity of these transporters at clinically relevant concentration to cause herb-drug interactions.

Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper.

BACKGROUND: 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2-1.0%. SUMMARY: Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. Key Messages: (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitoring.

Interaction of herbal products with prescribed medications: A systematic review and meta-analysis.

Although several studies on pharmacokinetic and/or pharmacodynamic herb-drug interactions (HDI) have been conducted in healthy volunteers, there is large uncertainty on the validity of these studies. A qualitative review and a meta-analysis were performed to establish the clinical evidence of these interaction studies. Out of 4026 screened abstracts, 32 studies were included into the qualitative analysis. The meta-analysis was performed on eleven additional studies. St. John's wort (SJW) significantly decreased the AUC (p < 0.0001) and clearance (p = 0.007) of midazolam. Further subgroup analysis identified age to affect Cmax of midazolam (p < 0.01) in the presence of SJW. Echinacea purpurea (EP) significantly increased the clearance of midazolam (p = 0.01). Evidence of publication bias (p > 0.001) was shown on the effect of the herbal products o half-life of midazolam. Green tea (GT) showed significant 85% decrease in plasma concentration of nadolol. The study findings suggest that GT, SJW and EP perpetuate significant interactions with prescribed medications via CYP3A4 or OATP1A2. Our studies show that meta-analyses are important in the area of natural products to provide necessary information on their use in overall medication plans in order to avoid unintended interactions.

Effects of folic acid supplementation on the pharmacokinetics and anticoagulant effect of warfarin: an open-label, prospective study of long-term administration in adults.

BACKGROUND: Folic acid supplementation in patients with folic acid deficiency has been associated with increased clearance of phenytoin to its cytochrome P450 (CYP) 2C9-mediated metabolite, 5-(4'-hydroxyphenyl)-5-phenylhydantoin. OBJECTIVE: The aim of this study was to determine whether folic acid supplementation increases the dosage requirement of the CYP2C9 substrate warfarin, and the formation clearance of the CYP2C9-mediated product, (S)-7-hydroxywarfarin. METHODS: Patients aged >or=18 years with folic acid deficiency who were receiving long-term treatment with a stable dosage of warfarin were studied prospectively, before and 30 to 60 days after the initiation of supplementation with folic acid. Warfarin dosage and international normalized ratio (INR) were documented, and the formation clearance of (S)- and (R)-7-hydroxywarfarin and the oral clearance of (S)- and (R)-warfarin were determined. RESULTS: Twenty-four white patients (14 males; mean (SD) age, 55.0 [19.7] years; body mass index, 30.64 [6.8] kg/m(2)) were enrolled. Treatment with folic acid was associated with a significantly increased mean (SD) formation clearance of (S)-7-hydroxywarfarin (1.096 [0.816] vs 1.608 [1.302] mL/min; P = 0.048). Before folic acid supplementation, the mean (SD) warfarin dosage was 5.98 (2.12) mg/d, and the INR was 2.51 (0.55). During supplementation, the warfarin dosage was 6.17 (2.31) mg/d and the INR was 2.63 (0.65) (both, P = NS vs before supplementation). CONCLUSIONS: Folic acid supplementation was associated with significantly increased formation clearance of (S)-7-hydroxywarfarin. Changes in warfarin dosage requirements and INR were nonsignificant.