ABSTRACT
Tamoxifen may lead to bothersome side effects contributing to non-compliance and decreased quality of life. Patients searching for relief are increasingly turning to cannabinoids such as CBD-oil. However, CBD-oil might affect tamoxifen pharmacokinetics (PK) through CYP2D6 inhibition. The aims of this open-label, single-arm study were (1) to determine the PK profile of tamoxifen when using CBD-oil, and (2) to subsequently investigate whether CBD-oil has a beneficial influence on side effects. Study patients had to have steady-state endoxifen concentrations ≥16 nM (conservative threshold). PK sampling and side effect assessment was done at initiation of CBD-oil and 28 days thereafter. Bio-equivalence could be concluded if the 90% confidence interval (CI) for the difference in endoxifen AUC fell within the [-20%; +25%] interval. The effect of CBD-oil on side effects was evaluated using the FACT-ES questionnaire. Endoxifen AUC decreased after CBD-oil by 12.6% (n = 15, 90% CI -18.7%, -6.1%) but remained within bio-equivalence boundaries. The endocrine sub-scale of the FACT-ES improved clinically relevant with 6.7 points (n = 26, p < 0.001) and health-related quality of life improved with 4.7 points after using CBD (95% CI + 1.8, +7.6). We conclude that CBD-oil, if of good quality and with a dosage below 50 mg, does not have to be discouraged in patients using it for tamoxifen-related side effects. Clinical trial registration: International Clinical Trial Registry Platform (NL8786; https://www.who.int/clinical-trials-registry-platform ).
ABSTRACT
Diffuse alveolar hemorrhage (DAH) is a fatal complication in patients with lupus. DAH can be induced in B6 mice by an intraperitoneal injection of pristane. Since human alpha-1-antitrypsin (hAAT) is an anti-inflammatory and immuno-regulatory protein, we investigated the protective effect of hAAT against pristane-induced DAH in B6 mice and hAAT transgenic (hAAT-Tg) mice. We first showed that hAAT Tg expression lowers TNF-α production in B cells, as well as CD4+ T cells in untreated mice. Conversely, the frequency of regulatory CD4+CD25+ and CD4+CD25-IL-10+ cells was significantly higher in hAAT-Tg than in B6 mice. This confirmed the anti-inflammatory effect of hAAT that was observed even at steady state. One week after a pristane injection, the frequency of peritoneal Ly6Chi inflammatory monocytes and neutrophils in hAAT-Tg mice was significantly lower than that in B6 mice. Importantly, pristane-induced DAH was completely prevented in hAAT-Tg mice and this was associated with a modulation of anti- to pro-inflammatory myeloid cell ratio/balance. We also showed that treatment with hAAT decreased the severity of DAH in B6 mice. These results showed for the first time that hAAT has a therapeutic potential for the treatment of DAH.
ABSTRACT
We, and others, have previously achieved high and sustained levels of transgene expression from viral vectors, such as recombinant adeno-associated virus (rAAV). However, regulatable transgene expression may be preferred in gene therapy for diseases, such as type 1 diabetes (T1D) and rheumatoid arthritis (RA), in which the timing and dosing of the therapeutic gene product play critical roles. In the present study, we generated a positive feedback regulation system for human alpha 1 antitrypsin (hAAT) expression in the rAAV vector. We performed quantitative kinetics studies in vitro and in vivo demonstrating that this vector system can mediate high levels of inducible transgene expression. Transgene induction could be tailored to occur rapidly or gradually, depending on the dose of the inducing drug, doxycycline (Dox). Conversely, after withdrawal of Dox, the silencing of transgene expression occurred slowly over the course of several weeks. Importantly, rAAV delivery of inducible hAAT significantly prevented T1D development in non-obese diabetic (NOD) mice. These results indicate that this Dox-inducible vector system may facilitate the fine-tuning of transgene expression, particularly for hAAT treatment of human autoimmune diseases, including T1D.
