It is known that co‐administration of CYP3A inducers may decrease the effectiveness of oral contraceptives containing progestins as mono‐preparations or combined with ethinylestradiol. In a randomized clinical drug‐drug interaction study, we investigated the effects of CYP3A induction on the pharmacokinetics of commonly used progestins and ethinylestradiol. Rifampicin was used to induce CYP3A. The progestins chosen as victim drugs were levonorgestrel, norethindrone, desogestrel, and dienogest as mono‐products, and drospirenone combined with ethinylestradiol. Postmenopausal women (n = 12–14 per treatment group) received, in fixed sequence, a single dose of the victim drug plus midazolam without rifampicin, with rifampicin 10 mg/day (weak induction), and with rifampicin 600 mg/day (strong induction). The effects on progestin exposure were compared with the effects on midazolam exposure (as a benchmark). Unbound concentrations were evaluated for drugs binding to sex hormone binding globulin. Weak CYP3A induction, as confirmed by a mean decrease in midazolam exposure by 46%, resulted in minor changes in progestin exposure (mean decreases: 15–37%). Strong CYP3A induction, in contrast, resulted in mean decreases by 57–90% (mean decrease in midazolam exposure: 86%). Namely, the magnitude of the observed induction effects varied from weak to strong. Our data might provide an impetus to revisit the currently applied clinical recommendations for oral contraceptives, especially for levonorgestrel and norethindrone‐containing products, and they might give an indication as to which progestin could be used, if requested, by women taking weak CYP3A inducers—although it is acknowledged that the exact exposure‐response relationship for contraceptive efficacy is currently unclear for most progestins.

Key Points• Lexaptepid modulates the inflammation-induced decrease in serum iron during experimental human endotoxemia.• Hepcidin targeting with the novel compound lexaptepid may be a viable approach to the treatment of anemia of inflammation in humans.Increased hepcidin production is key to the development of anemia of inflammation. We investigated whether lexaptepid, an antihepcidin L-oligoribonucleotide, prevents the decrease in serum iron during experimental human endotoxemia. This randomized, doubleblind, placebo-controlled trial was carried out in 24 healthy males. At T 5 0 hours, 2 ng/kg Escherichia coli lipopolysaccharide was intravenously administered, followed by an intravenous injection of 1.2 mg/kg lexaptepid or placebo at T 5 0.5 hours. The lipopolysaccharide-induced inflammatory response was similar in subjects treated with lexaptepid or placebo regarding clinical and biochemical parameters. At T 5 9 hours, serum iron had increased by 15.9 6 9.8 mmol/L from baseline in lexaptepidtreated subjects compared with a decrease of 8.3 6 9.0 mmol/L in controls (P < .0001). This study delivers proof of concept that lexaptepid achieves clinically relevant hepcidin inhibition enabling investigations in the treatment of anemia of inflammation. This trial was registered at www.clinicaltrial.gov as #NCT01522794. (Blood. 2014;124(17):2643-2646

No abstract

Olaptesed pegol (NOX-A12) is a pegylated structured L-oligoribonucleotide that binds and neutralizes CXCL12, a chemokine tightly regulating the life cycle of chronic lymphocytic leukemia cells. The resulting inhibition of CXCR4 and CXCR7 signaling reduces the protective activity of the bone marrow and lymph node microenvironment. CXCL12 inhibition mobilizes chronic lymphocytic leukemia cells into the circulation and prevents their homing into the protective niches. In this phase I/II study, 28 patients with relapsed/refractory chronic lymphocytic leukemia were treated with olaptesed pegol in combination with bendamustine and rituximab. Combination treatment was preceded by single escalating pilot doses of olaptesed pegol in the first ten patients for evaluation of safety and pharmacokinetics. Peak concentrations and systemic exposure of olaptesed pegol were dose-linear; plasma elimination was monophasic with a 53.2 h half-life. A rapid increase in circulating chronic lymphocytic leukemia cells was observed already 1 h after administration of olaptesed pegol and lasted for at least 72 h. Single-agent treatment was well tolerated and no dose-limiting toxicity was observed. The combination regimen yielded an overall response rate of 86%, with 11% of patients achieving a complete response and 75% a partial response. Notably, all ten high-risk patients, including four with a 17p deletion, responded to treatment. The median progression-free survival was 15.4 (95% confidence interval: 12.2, 26.2) months while the median overall survival was not reached with >80% of patients alive after a median follow-up of 28 months. Olaptesed pegol was well tolerated and did not result in additional toxicity when combined with bendamustine and rituximab (ClinicalTrials.gov identifier: NCT01486797). Further clinical development of this novel CXCL12 inhibitor is thus warranted.

Background and PurposeAnaemia of chronic disease is characterized by impaired erythropoiesis due to functional iron deficiency, often caused by excessive hepcidin. Lexaptepid pegol, a pegylated structured l‐oligoribonucleotide, binds and inactivates hepcidin.Experimental ApproachWe conducted a placebo‐controlled study on the safety, pharmacokinetics and pharmacodynamics of lexaptepid after single and repeated i.v. and s.c. administration to 64 healthy subjects at doses from 0.3 to 4.8 mg·kg−1.Key ResultsAfter treatment with lexaptepid, serum iron concentration and transferrin increased dose‐dependently. Iron increased from approximately 20 μmol·L−1 at baseline by 67% at 8 h after i.v. infusion of 1.2 mg·kg−1 lexaptepid. The pharmacokinetics showed dose‐proportional increases in peak plasma concentrations and moderately over‐proportional increases in systemic exposure. Lexaptepid had no effect on hepcidin production or anti‐drug antibodies. Treatment with lexaptepid was generally safe and well tolerated, with mild and transient transaminase increases at doses ≥2.4 mg·kg−1 and with local injection site reactions after s.c. but not after i.v. administration.Conclusions and ImplicationsLexaptepid pegol inhibited hepcidin and dose‐dependently raised serum iron and transferrin saturation. The compound is being further developed to treat anaemia of chronic disease.

The new OECD guideline 429 (skin sensitization: local lymph node assay) is based upon a protocol, which utilises the incorporation of radioactivity into DNA as a measure for cell proliferation in vivo. The guideline also enables the use of alternative endpoints in order to assess draining lymph node (LN) cell proliferation. Here we describe the first round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in seven laboratories. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products, Swissmedic. Statistical analyses of all data were performed by an independent centre at the University of Bern, Department of Statistics. Ear-draining, LN weight and cell count were used to assess proliferation instead of radioactive labeling of lymph node cells. In addition, the acute inflammatory skin reaction was measured by ear swelling and weight of circular biopsies of the ears to identify skin irritating properties of the test items. Hexylcinnamaldehyde (HCA) and three blinded test items were applied to female, 8--10 weeks old NMRI and BALB/c mice. Results were sent via the independent study coordinator to the statistician. The results of this first round showed that the alternative endpoints of the LLNA are sensitive and robust parameters. The use of ear weights added an important parameter assessing the skin irritation potential, which supports the differentiation of pure irritative from contact allergenic potential. There were absolute no discrepancies between the categorisation of the three test substances A--C determined by each single participating laboratories. The results highlighted also that many parameters do have an impact on the strength of the responses. Therefore, such parameters have to be taken into consideration for the categorisation of compounds due to their relative sensitizing potencies.

No abstract

Epidemiological studies have suggested an association between exposure to dioxins and cardiovascular morbidity and mortality. However, cardiotoxic effects of low doses of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) in animals have not been reported so far. We studied the hearts of male marmosets ( Callithrix jacchus)after treatment with single subcutaneous doses of 1, 10 or 100 ng TCDD/kg body weight or vehicle (toluene/DMSO 1+2 v/v, 100 microl/kg body weight). The animals were killed 2 or 4 weeks after treatment. Tissue samples of left ventricular myocardium were stained with picrosirius red and examined histologically along with quantitative image analysis. Extracellular matrix proteins were additionally analysed by western blotting. Monkeys showed no overt signs of toxicity nor did their relative heart weights differ significantly depending on treatment. Histology revealed an increase of picrosirius red-positive area above control values in 2 of 4 (1 ng TCDD/kg body weight), 6 of 12 (10 ng/kg) and 6 of 10 (100 ng/kg) marmosets. Western blotting confirmed these histological findings showing an increase of collagen, fibronectin and laminin in the hearts of TCDD-treated animals. Western blotting additionally showed an increased concentration of transforming growth factor beta1 (TGF-beta1) as well as TGF-beta receptor type I which could be a functional link to the effects on extracellular matrix. Our findings might explain the association of TCDD exposure with increased cardiovascular mortality observed in epidemiological studies and should stimulate further research on the role of changes in the extracellular matrix in the toxic effects of dioxins and related substances on other organs.