The addition of twice-weekly azithromycin significantly decreased the incidence of exacerbation and 24-hour sputum volume and may have stabilized the PFTs and PFs in this 11-patient pilot study. The results of this study justify further investigation of adding azithromycin to the treatment regimens of patients with bronchiectasis for its disease-modifying effects.

Background Hereditary transthyretin (ATTRv) amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We aimed to assess the efficacy and safety of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with ATTRv amyloidosis with polyneuropathy. MethodsThis multi-country, multi-centre, open-label extension (OLE) trial enrolled patients at 43 sites in 19 countries as of 24 September 2018. Patients were eligible if they had completed the phase 3 APOLLO (randomised, double-blind, placebo-controlled [2:1], 18-month study) or phase 2 OLE (single-arm, 24-month study) parent studies and tolerated the study drug. Eligible patients from APOLLO (APOLLO-patisiran [received patisiran during APOLLO] and APOLLO-placebo [received placebo during APOLLO] groups) and the phase 2 OLE (phase 2 OLE patisiran group) studies enrolled in this Global OLE trial and receive patisiran 0•3 mg/kg by intravenous infusion every 3 weeks for up to 5 years. Efficacy assessments include measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress. Patients included in the current efficacy analyses are those who had completed 12-month efficacy assessments as of the data cut-off. Safety analyses included all patients who received ≥1 dose of patisiran up to the data cut-off. The Global OLE is ongoing with no new enrolment, and current findings are based on the 12-month interim analysis. The study is registered with ClinicalTrials.gov, NCT02510261.

Fluoroquinolones are known to interact with drugs containing multivalent ions. Current Food and Drug Administration (FDA) labeling states that ciprofloxacin and most other fluoroquinolones are safe to be given with food and dietary calcium but not calcium supplements. Although many of the currently marketed calcium fortified foods have calcium contents that usually exceed those in dietary calcium sources, it is unclear whether they represent a risk for less than optimal absorption of fluoroquinolones, which may result in subsequent clinical failures due to lack of bacterial eradication and antibiotic resistance. The purpose of this three-way, randomized, crossover study was to characterize and compare the bioequivalence of single doses of oral ciprofloxacin in 15 healthy volunteers when administered with water, concurrently with orange juice, and concurrently with calcium-fortified orange juice. Compared to the control arm, the Cmax of ciprofloxacin significantly decreased when it was given with orange juice (23%, p = 0.001) and with calcium-fortified orange juice (41%, p < 0.001). Twenty-four-hour ciprofloxacin AUCs were also decreased for both forms of the orange juice (22% [p < 0.001] and 38% [p < 0.001], respectively). When compared to each other, neither of the orange juice regimens were bioequivalent to each other, with the Cmax and AUC for the fortified form being 22% (p = 0.005) and 21% (p = 0.015) lower than those of the nonfortified form. By FDA standards, although ciprofloxacin is marginally bioequivalent when administered with orange juice, it is not when it is administered with calcium-fortified orange juice. The changes in Cmax and AUC have the potential to significantly decrease clinical efficacy and promote antibiotic resistance. Not warning patients about potential food-drug interactions with fortified foods may be a major unrealized and unstudied inadvertent source of clinical failures and resistance trends with fluoroquinolones.

The effects of a common oral contraceptive preparation on the activity of 7 drug-metabolizing enzymes were investigated using the validated Cooperstown 5+1 Cocktail. In a randomized crossover fashion, 10 premenopausal women received caffeine, dextromethorphan, omeprazole, intravenous midazolam, and warfarin + vitamin K with and without a triphasic oral contraceptive (ethinyl estradiol 35 microg) and varying doses of daily norgestimate (0.18, 0.215, and 0.25 mg). Bioequivalence testing showed nonequivalence in drug versus no-drug treatment on the activity of drug-metabolizing enzymes (as reflected by metabolite ratios following probe drug administration); the activity of CYP1A2, CYP2C19, and NAT-2 decreased following the oral contraceptive, whereas the activity of CYP2C9 and CYP2D6 increased. No effects on xanthine oxidase or hepatic CYP3A were seen. Application of a non-parametric statistical testing approach revealed a significant difference only for CYP1A2 and CYP2C19. This triphasic oral contraceptive may have a clinically significant effect on the activity of some drug-metabolizing enzymes.

Chelation interactions between drugs/supplements that contain large amounts of multivalent ions and the fluoroquinolones have been known for quite some time. However, there has been a lack of taking this interaction into account when they may be coadministered with foods that have been fortified with amounts of multiple multivalent ions that equal or exceed many supplement products. A previous study demonstrated that 12 ounces of calcium-fortified orange juice significantly decreased the bioequivalence of a dose of ciprofloxacin. This study examined, in 16 healthy volunteers, whether 12 ounces of orange juice with and without calcium fortification would demonstrate the same chelation interaction with single doses of levofloxacin. The results of the study demonstrated that both types of juice decreased levofloxacin Cmax values by 14% to 18% and prolonged tmax values by approximately 50%, with calcium-fortified orange juice decreasing Cmax enough to lose bioequivalence as compared to the control arm (89% [78.1%, 99.8%]). Due to the lack of change in overall exposure, it is thought that rather than a chelation interaction, levofloxacin and components of the orange juices competed for intestinal transport mechanisms such as P-glycoprotein and organic anion-transporting polypeptides, which resulted in the discovered interaction. These results further confirm the need to adjust regulatory studies to include bioequivalence/bioavailability studies that contain fortified foods more than high-calorie/high-fat foods to better reflect current American consumption habits.