22 research outputs found
Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers
Aims
Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers.
Methods
A randomized placebo‐controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing.
Results
Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma Cmax, AUC, clearance, elimination half‐life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t‐tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05–0.08 μm and 0.6 μm, respectively).
Conclusion
The results indicate that short term use of this piperine‐enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes
Slow Accumulation and Elimination of Diazepam and Its Active Metabolite With Extended Treatment in the Elderly
Systematic Study of the Glutathione (GSH) Reactivity of <i>N</i>‑Arylacrylamides: 1. Effects of Aryl Substitution
Success
in the design of targeted covalent inhibitors depends in
part on a knowledge of the factors influencing electrophile reactivity.
In an effort to further develop an understanding of structure–reactivity
relationships among <i>N</i>-arylacrylamides, we determined
glutathione (GSH) reaction rates for a family of <i>N</i>-arylacrylamides independently substituted at ortho-, meta-, and
para-positions with 11 different groups common to inhibitor design.
We find that substituent effects on reaction rates show a linear Hammett
correlation for ortho-, meta-, and para-substitution. In addition,
we note a correlation between <sup>1</sup>H and <sup>13</sup>C NMR
chemical shifts of the acrylamide with GSH reaction rates, suggesting
that NMR chemical shifts may be a convenient surrogate measure of
relative acrylamide reactivity. Density functional theory calculations
reveal a correlation between computed activation parameters and experimentally
determined reaction rates, validating the use of such methodology
for the screening of synthetic candidates in a prospective fashion
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CRISPR/Cas9 Mediated Disruption of the Swedish APP Allele as a Therapeutic Approach for Early-Onset Alzheimer’s Disease
The APPswe (Swedish) mutation in the amyloid precursor protein (APP) gene causes dominantly inherited Alzheimer’s disease (AD) as a result of increased β-secretase cleavage of the amyloid-β (Aβ) precursor protein. This leads to abnormally high Aβ levels, not only in brain but also in peripheral tissues of mutation carriers. Here, we selectively disrupted the human mutant APPSW allele using CRISPR. By applying CRISPR/Cas9 from Streptococcus pyogenes, we generated allele-specific deletions of either APPSW or APPWT. As measured by ELISA, conditioned media of targeted patient-derived fibroblasts displayed an approximate 60% reduction in secreted Aβ. Next, coding sequences for the APPSW-specific guide RNA (gRNA) and Cas9 were packaged into separate adeno-associated viral (AAV) vectors. Site-specific indel formation was achieved both in primary neurons isolated from APPSW transgenic mouse embryos (Tg2576) and after co-injection of these vectors into hippocampus of adult mice. Taken together, we here present proof-of-concept data that CRISPR/Cas9 can selectively disrupt the APPSW allele both ex vivo and in vivo—and thereby decrease pathogenic Aβ. Hence, this system may have the potential to be developed as a tool for gene therapy against AD caused by APPswe and other point mutations associated with increased Aβ
The Effect of Equisetum Arvense (Horse Tail) Ointment on Wound Healing and Pain Intensity After Episiotomy: A Randomized Placebo-Controlled Trial
High levels of AAV vector integration into CRISPR-induced DNA breaks
Adeno-associated virus (AAV) vectors have shown promising results in preclinical models, but the genomic consequences of transduction with AAV vectors encoding CRISPR-Cas nucleases is still being examined. In this study, we observe high levels of AAV integration (up to 47%) into Cas9-induced double-strand breaks (DSBs) in therapeutically relevant genes in cultured murine neurons, mouse brain, muscle and cochlea. Genome-wide AAV mapping in mouse brain shows no overall increase of AAV integration except at the CRISPR/Cas9 target site. To allow detailed characterization of integration events we engineer a miniature AAV encoding a 465 bp lambda bacteriophage DNA (AAV-lambda 465), enabling sequencing of the entire integrated vector genome. The integration profile of AAV-465 lambda in cultured cells display both full-length and fragmented AAV genomes at Cas9 on-target sites. Our data indicate that AAV integration should be recognized as a common outcome for applications that utilize AAV for genome editing