Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride:the PATHWAY-2 mechanisms substudies

Background: In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension. Methods: PATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25–50 mg, bisoprolol 5–10 mg, and doxazosin 4–8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10–20 mg once daily on clinic systolic blood pressure during an optional 6–12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008–007149–30, and ClinicalTrials.gov, number NCT02369081. Findings: Of the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r2=0·13, p<0·0001) and plasma renin (r2=0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17–33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from baseline (95% CI 4·0 to 8·8; p<0·0001) with spironolactone, but not other treatments. Amiloride (10 mg once daily) reduced clinic systolic blood pressure by 20·4 mm Hg (95% CI 18·3–22·5), compared with a reduction of 18·3 mm Hg (16·2–20·5) with spironolactone (25 mg once daily). No serious adverse events were recorded, and adverse symptoms were not systematically recorded after the end of the double-blind treatment. Mean plasma potassium concentrations increased from 4·02 mmol/L (95% CI 3·95–4·08) on placebo to 4·50 (4·44–4·57) on amiloride (p<0·0001). Interpretation: Our results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension

High-throughput screening of excipients with a biological effect: a kinetic study on the effects of surfactants on efflux-mediated transport

Objective In this study, we develop and apply a high-throughput screening protocol to investigate the activity of non-ionic surfactants, with a broad range of hydrophilic–lipophilic balance values, against ABCB1-mediated efflux transport and ABCC2-mediated efflux transport. Methods Caco-2 cells were grown for 7 days in 96-well plates, then washed and incubated with the test materials for 2 h in the presence of 2.5 lM of either rhodamine 123 (R-123) or 5(6)-Carboxy-20,70 dichlorofluorescein diacetate as probes of ABCB1 and ABCC2, respectively. Key findings Of the surfactants tested, no activity against ABCC2 was detected and all surfactants showing efficacy against ABCB1 had a HLB value of 22 or below. Inhibition of ABCB1 was seen in the order of efficacy to be poloxamer 335 > poloxamer 40 > Crovol A-70 > Myrj S-40 > poloxamer 184 > poloxamer 182 > Etocas 40 > Tween 20 > Etocas 29 > Tween 80 > Acconon C-44 > Span 20. With regard to this inhibition, the distribution of hydrophilic regions is more important than the HLB value. Conclusion This work demonstrates a high-throughput protocol for detecting materials that can modulate ABCB1-mediated efflux. These surfactants could be exploited to improve oral delivery of drugs prone to efflux

Pregnane X receptor regulates drug metabolism and transport in the vasculature and protects from oxidative stress

Aims Circulating endogenous, dietary and foreign chemicals can contribute to vascular dysfunction. The mechanism by which the vasculature protects itself from these chemicals is unknown. This study investigates whether the pregnane X receptor (PXR), the major transcriptional regulator of hepatic drug metabolism and transport that responds to such xenobiotics, mediates vascular protection by co-ordinating a defence gene program in the vasculature.Methods and Results PXR was detected in primary human and rat aortic endothelial and smooth muscle cells and blood vessels including human and rat aorta. Metabolic PXR target genes cytochrome P450 3A, 2B, 2C and glutathione-S-transferase mRNA and activity were induced by PXR ligands in rodent and human vascular cells and absent in the aortas from PXR null mice stimulated in vivo or in rat aortic smooth muscle cells expressing dominant negative PXR. Activation of aortic PXR by classical agonists had several protective effects; increased xenobiotic metabolism demonstrated by bio-activation of the pro-drug clopidogrel, which reduced adenosine diphosphate-induced platelet aggregation; increased expression of multidrug resistance protein 1, mediating chemical efflux from the vasculature; and protection from reactive oxygen species-mediated cell death.Conclusions PXR co-ordinately up-regulates drug metabolism, transport and anti-oxidant genes to protect the vasculature from endogenous and exogenous insults, thus representing a novel gatekeeper for vascular defence

Succesvolle ambulante behandeling van patiënten met harige-cellenleukemie met één cyclus van het purineanalogon cladribine

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