Pulmonary hypertension secondary to bronchopulmonary dysplasia (BPD-PH) represents a major complication of BPD in extremely preterm infants for which there are currently no safe and effective interventions. The abundance of interleukin-1 (IL-1) is strongly correlated with the severity and long-term outcome of BPD infants and we have previously shown that IL-1 receptor antagonist (IL-1Ra) protects against murine BPD; therefore, we hypothesized that IL-1Ra may also be effective against BPD-PH. We employed daily injections of IL-1Ra in a murine model in which BPD/BPD-PH was induced by antenatal LPS and postnatal hyperoxia of 65% O2. Pups reared in hyperoxia for 28 days exhibited a BPD-PH-like disease accompanied by significant changes in pulmonary vascular morphology: micro-CT revealed an 84% reduction in small vessels (4-5 μm diameter) compared to room air controls; this change was prevented by IL-1Ra. Pulmonary vascular resistance, assessed at day 28 of life by echocardiography using the inversely-related surrogate marker time-to-peak-velocity/right ventricular ejection time (TPV/RVET), increased in hyperoxic mice (0.27 compared to 0.32 in air controls), and fell significantly with daily IL-1Ra treatment (0.31). Importantly, in vivo cine-angiography revealed that this protection afforded by IL-1Ra treatment for 28 days is maintained at day 60 of life. Despite an increased abundance of mediators of pulmonary angiogenesis in day 5 lung lysates, namely vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1), no difference was detected in ex vivo pulmonary vascular reactivity between air and hyperoxia mice as measured in precision cut lung slices, or by immunohistochemistry in alpha-smooth muscle actin (α-SMA) and endothelin receptor type-A (ETA) at day 28. Further, on day 28 of life we observed cardiac fibrosis by Sirius Red staining, which was accompanied by an increase in mRNA expression of galectin-3 and CCL2 (chemokine (C-C motif) ligand 2) in whole hearts of hyperoxic pups, which improved with IL-1Ra. In summary, our findings suggest that daily administration of the anti-inflammatory IL-1Ra prevents the increase in pulmonary vascular resistance and the pulmonary dysangiogenesis of murine BPD-PH, thus pointing to IL-1Ra as a promising candidate for the treatment of both BPD and BPD-PH.
Bile acid synthesis defects (BASDs) comprise a group of rare diseases that can be severely disabling. Bile acid supplementation with 5 to 15 mg/kg cholic acid (CA) has been hypothesized to decrease endogenous bile acid production, stimulate bile secretion, and improve bile flow and micellar solubilization, thereby improving the biochemical profile and potentially slowing down disease progression. Currently, CA treatment is unavailable in the Netherlands, and CA capsules were compounded by the Amsterdam UMC Pharmacy from CA raw material. This study aims to determine the pharmaceutical quality and stability of the pharmacy compounded CA capsules. Pharmaceutical quality tests were performed on 25 mg and 250 mg CA capsules according to general monographs of the European Pharmacopoeia 10th ed. For the stability study, the capsules were stored under long-term conditions (25 °C ± 2 °C/60% ± 5% RH) and accelerated conditions (40 °C ± 2 °C/75% ± 5% RH). Samples were analyzed at 0, 3, 6, 9 and 12 months. The findings demonstrate that the pharmacy compounded CA capsules within a range of 25-250 mg that complied with the European regulations in regard to product quality and safety. The pharmacy compounded CA capsules are suitable for use in patients with BASD, as clinically indicated. With its simple formulation, pharmacies are provided a guidance on product validation and stability testing when commercial CA capsules are unavailable.
Abstract The spice curcumin and its metabolites have been linked to many beneficial health effects. These effects have, thus far, not been duplicated in independent research most likely due to low plasma concentrations of curcumin. Despite the many reports, the public’s interest in curcumin continues to grow and many people use curcumin in daily life. Moreover, companies seize the popularity of curcumin and claim that their formulations increase systemic expose of curcumin. In this independent study we determined the plasma concentration of curcumin after oral intake in daily life to determine if the systemic exposure is sufficient to achieve beneficial health effects. We used a validated HPLC-MS/MS assay to determine the plasma concentration of curcumin and its metabolites in 47 individuals (patient or healthy) using their own curcumin formulations. Through questionnaires, we assessed which other supplements and (self-)medication(s) were used. The concentrations of curcumin and its metabolites were analyzed in plasma samples collected just before and 1.5 h after curcumin intake. Each sample was pretreated with and without β-glucuronidase to determine the levels of conjugated and unconjugated curcumin. After oral intake of the curcumin supplement, plasma concentrations of curcumin, demethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin ranged between 2 and 4 nM. Use of adjuvants like piperine did not result in higher curcumin plasma concentrations. Adding β-glucuronidase to the plasma sample increased curcumin plasma levels from below LLQ to 25.3 ng/mL, however still below any plasma concentration to which a beneficial health effect can be expected. The observed plasma concentration of unchanged curcumin remained several orders below the concentration of 2-100 μg/mL used in in vitro studies. Therefore, our study confirms the low plasma levels of curcumin and indicates the need to be critical towards the claimed beneficial systemic health effects of current curcumin supplement use in daily life among patients and healthy individuals.
The spice curcumin and its metabolites are widely used by cancer patients but have not shown proven health benefits in clinical studies, likely due to low plasma concentrations after oral intake. However, public interest in curcumin continues to grow, and companies claim enhanced absorption in their formulations. This study aims to determine if daily oral intake of curcumin leads to sufficient plasma concentrations for health effects. The study was registered in the Dutch Clinical Trial Register with ID NL5931.We used a validated HPLC-MS/MS method to measure curcumin and its metabolites in 47 individuals using their own curcumin formulations. Questionnaires assessed other supplement and medication use. Plasma samples were collected before and 1.5 h after intake, analyzing curcumin and metabolite levels with and without β-glucuronidase pretreatment to measure conjugated and unconjugated forms.Plasma concentrations of curcumin, demethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin, ranged between 1.0 and 18.6 ng/mL. Adding β-glucuronidase resulted in an increase of unconjugated curcumin plasma levels to 25.4 ng/mL; however still significantly below (1000-fold) a plasma concentration that is expected to have a beneficial health effect. The use of adjuvants like piperine did not result in higher curcumin plasma concentrations.Our study shows that using oral curcumin supplements still does not result in therapeutic plasma levels. Health care practitioners need to be critical toward the claimed beneficial systemic health effects of current curcumin supplement use by their patients.https://onderzoekmetmensen.nl/en/trial/25480, NL5931.
BackgroundThe spice curcumin is supposed to have many different beneficial health effects. To understand the complete pharmacokinetics of curcumin we need an analytical method to determine curcumin and its metabolites in human plasma, urine or feces. We have developed an HPLC-MS/MS method for the simultaneous analysis of curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and piperine in human plasma, urine or feces.MethodsSample pretreatment involved a simple liquid-liquid extraction with tert-butyl methyl ether. Conjugated curcumin and analogs can be measured after enzymatic hydrolysis. Reversed-phase chromatography with a linear gradient of 50–95% methanol in 0.1% formic acid was used. Total run time is 15 min. The method was validated with regards to stability, specificity, sensitivity, linearity, accuracy, repeatability and reproducibility. The applicability of the method was tested using actual patients samples.ResultsThe LLOQ in plasma, urine and feces for curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and piperine ranged from 1 to 5 nM. Whereas all compounds could be quantified on a linear range between 2 and 400 nM. Plasma and feces recovery of curcumin was 97.1 ± 3.7% and 99.4 ± 16.2%, whereas urine showed a recovery of 57.1 ± 9.3%. All compounds had acceptable in-between day or between day variability in the different matrixes.ConclusionA HPLC-MS/MS method was developed and validated for the simultaneous quantification of curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and piperine in human plasma, urine or feces. This method will aid in critically verifying the pharmacokinetics of curcumin made by supplement manufacturers and help us to provide insight in the claimed bioavailability of curcumin supplements.
Abstract Background The retina is increasingly recognized as a promising target to identify early changes associated with Alzheimer’s disease (AD). Previous studies showed presence of retinal amyloid in AD patients in‐vivo as well as in post‐mortem retinal tissue of AD patients. The objective of this study is to non‐invasively discriminate AD patients from controls with fluorescent retinal imaging, using curcumin as labeling fluorophore. Method 26 AD patients (age 66( + 9), MMSE≥18) and 14 controls (age 71( + 12)) were enrolled from a tertiary memory clinic. Subjects were confirmed amyloid positive or negative based on CSF analysis and/or amyloid PET. We used three curcumin formulations: Longvida (10 days 4000 mg), Theracurmin (5 days 180 mg) and Novasol (4 days 300 mg). Plasma levels of curcumin and its derivatives were determined. Baseline and follow up scans of 2‐6 retinal regions were performed with blue autofluorescence imaging (λ = 486nm). Retinal images were visually assessed in a multidisciplinary setting. In addition a selection of retinal scans of participants receiving Longvida and Novasol were quantitatively analyzed. Result Plasma analysis yielded mean curcumin levels of 198.7 (±143.4) with Longvida, 576.6 nM, (±211.5) with Theracurmin and 1605.8 nM (±524.6) with Novasol. Visual analysis of baseline images showed no focal hyperfluorescence or other changes in AD‐patients compared to controls. Also, no differences were found when comparing pre‐and post‐curcumin images within AD patients and controls. Quantitative analyses confirmed a similar amount of focal hyperfluorescent spots in AD patients and controls. In addition no difference in increase of focal hyperfluorescence after curcumin intake could discriminate between AD patients and controls. Conclusion We found no focal retinal hyperfluorescence in AD patients or controls pre‐and post curcumin, even when using curcumin formulations that yielded higher plasma levels than Longvida, a formulation previously successfully used for this purpose. Implication: More and more initiatives are taken to assess retinal amyloid in AD patients and currently even commercial scans are brought to the market. We could not confirm that retinal changes described in previous studies represent retinal amyloid, and we were unable to replicate previous work discriminating AD patients from controls based on retinal amyloid visualization.
Transgender women who underwent gonadectomy have lower serum testosterone concentrations than cisgender women. There is uncertainty regarding the dosing and side effects of supplementation of testosterone in transgender women. This study aimed to assess the feasibility of dosing testosterone to the cisgender female physiological range in transgender women. In addition, we explored changes in cardiovascular parameters, virilizing side effects, and clinical symptoms.
Abstract INTRODUCTION Previous work showed the in-vivo presence of retinal amyloid in AD patients using curcumin. We aimed to replicate these findings in an amyloid biomarker confirmed cohort. METHODS Twenty-six AD patients (age 66 (+9), MMSE≥17) and 14 controls (age 71(+12)) used one of three curcumin formulations: Longvida ® , Theracurmin ® and Novasol ® . Plasma levels were determined and pre- and post-curcumin retinal fluorescence scans were visually assessed in all cases and quantitatively assessed in a subset. RESULTS Visual assessment showed no difference between AD patients and controls for pre- and post-curcumin images. This was confirmed by quantitative analyses on a subset. Mean conjugated plasma curcumin levels were 198.7 nM (Longvida ® ), 576.6 nM (Theracurmin ® ) and 1605.8 nM (Novasol ® ). DISCUSSION We found no difference in retinal fluorescence betweenamyloid confirmed AD cases and control participants, using Longvida ® and two additional curcumin formulations. Additional replication studies in amyloid confirmed cohorts are needed to assess the diagnostic value of retinal fluorescence as an AD biomarker.
Background The spice curcumin is supposed to have many different beneficial health effects. To understand the complete pharmacokinetics of curcumin we need an analytical method to determine curcumin and its metabolites in human plasma, urine or feces. We have developed an HPLC-MS/MS method for the simultaneous analysis of curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and piperine in human plasma, urine or feces.Methods Sample pretreatment involved a simple liquid-liquid extraction with tert -butyl methyl ether. Conjugated curcumin and analogs can be measured after enzymatic hydrolysis. Reversed-phase chromatography with a linear gradient of 50 to 95% methanol in 0.1% formic acid was used. Total run time is 15 minutes. The method was validated with regards to stability, specificity, sensitivity, linearity, accuracy, repeatability and reproducibility. The applicability of the method was tested using actual patients samples.Results The LLOQ in plasma, urine and feces for curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and piperine ranged from 1-5 nM. Whereas all compounds could be quantified on a linear range between 2-400 nM. Plasma and feces recovery of curcumin was 96.7±16.7% and 109.2± 38.5%, whereas urine showed a recovery of 74.1± 7.6%. All compounds had acceptable in-between day or between day variability in the different matrixes.Conclusion A HPLC-MS/MS method was developed and validated for the simultaneous quantification of curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and piperine in human plasma, urine or feces. This method will aid in critically verifying the pharmacokinetics of curcumin made by supplement manufacturers and help us to provide insight in the claimed bioavailability of curcumin supplements.
Previous work has showed the in vivo presence of retinal amyloid in Alzheimer's disease (AD) patients using curcumin. We aimed to replicate these findings in an amyloid biomarker-confirmed cohort.
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