Background

Gastroesophageal reflux and microaspiration (MA) of gastric juice are associated with various human respiratory diseases but not in dogs.

Objective

To detect the presence of bile acids in bronchoalveolar lavage fluid (BALF) of dogs with various respiratory diseases.

Animals

Twenty-seven West Highland White Terriers (WHWTs) with canine idiopathic pulmonary fibrosis (CIPF), 11 dogs with bacterial pneumonia (BP), 13 with chronic bronchitis (CB), 9 with eosinophilic bronchopneumopathy (EBP), 19 with laryngeal dysfunction (LD), 8 Irish Wolfhounds (IWHs) with previous BPs, 13 healthy WHWTs, all privately owned dogs, and 6 healthy research colony Beagles METHODS: Prospective cross-sectional observational study with convenience sampling of dogs. Bile acids were measured by mass spectrometry in BALF samples. Total bile acid (TBA) concentration was calculated as a sum of 17 different bile acids.

Results

Concentrations of TBA were above the limit of quantification in 78% of CIPF, 45% of BP, 62% of CB, 44% of EBP, 68% of LD, and 13% of IWH dogs. In healthy dogs, bile acids were detected less commonly in Beagles (0/6) than in healthy WHWTs (10/13). Concentrations of TBA were significantly higher in CIPF (median 0.013 μM, range not quantifiable [n.q.]-0.14 μM, P < .001), healthy WHWTs (0.0052 μM, n.q.-1.2 μM, P = .003), LD (0.010 μM, n.q.-2.3 μM, P = .015), and CB (0.0078 μM, n.q.-0.073 μM, P = .018) groups compared to Beagles (0 μM, n.q.).

Conclusion and clinical importance

These results suggest that MA occurs in various respiratory diseases of dogs and also in healthy WHWTs.

BACKGROUND: The World Health Organization recommendation on the use of a single low dose of primaquine (SLD-PQ) to reduce Plasmodium falciparum malaria transmission requires more safety data. METHODS: We conducted an open-label, nonrandomized, dose-adjustment trial of the safety of 3 single doses of primaquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient adult males in Mali, followed by an assessment of safety in G6PD-deficient boys aged 11-17 years and those aged 5-10 years, including G6PD-normal control groups. The primary outcome was the greatest within-person percentage drop in hemoglobin concentration within 10 days after treatment. RESULTS: Fifty-one participants were included in analysis. G6PD-deficient adult males received 0.40, 0.45, or 0.50 mg/kg of SLD-PQ. G6PD-deficient boys received 0.40 mg/kg of SLD-PQ. There was no evidence of symptomatic hemolysis, and adverse events considered related to study drug (n = 4) were mild. The mean largest within-person percentage change in hemoglobin level between days 0 and 10 was -9.7% (95% confidence interval [CI], -13.5% to -5.90%) in G6PD-deficient adults receiving 0.50 mg/kg of SLD-PQ, -11.5% (95% CI, -16.1% to -6.96%) in G6PD-deficient boys aged 11-17 years, and -9.61% (95% CI, -7.59% to -13.9%) in G6PD-deficient boys aged 5-10 years. The lowest hemoglobin concentration at any point during the study was 92 g/L. CONCLUSION: SLD-PQ doses between 0.40 and 0.50 mg/kg were well tolerated in G6PD-deficient males in Mali. CLINICAL TRIALS REGISTRATION: NCT02535767.

BACKGROUND: Single low doses of primaquine, when added to artemisinin-based combination therapy, might prevent transmission of Plasmodium falciparum malaria to mosquitoes. We aimed to establish the activity and safety of four low doses of primaquine combined with dihydroartemisinin-piperaquine in male patients in Mali. METHODS: In this phase 2, single-blind, dose-ranging, adaptive randomised trial, we enrolled boys and men with uncomplicated P falciparum malaria at the Malaria Research and Training Centre (MRTC) field site in Ouelessebougou, Mali. All participants were confirmed positive carriers of gametocytes through microscopy and had normal function of glucose-6-phosphate dehydrogenase (G6PD) on colorimetric quantification. In the first phase, participants were randomly assigned (1:1:1) to one of three primaquine doses: 0 mg/kg (control), 0·125 mg/kg, and 0·5 mg/kg. Randomisation was done with a computer-generated randomisation list (in block sizes of six) and concealed with sealed, opaque envelopes. In the second phase, different participants were sequentially assigned (1:1) to 0·25 mg/kg primaquine or 0·0625 mg/kg primaquine. Primaquine tablets were dissolved into a solution and administered orally in a single dose. Participants were also given a 3 day course of dihydroartemisinin-piperaquine, administered by weight (320 mg dihydroartemisinin and 40 mg piperaquine per tablet). Outcome assessors were masked to treatment allocation, but participants were permitted to find out group assignment. Infectivity was assessed through membrane-feeding assays, which were optimised through the beginning part of phase one. The primary efficacy endpoint was the mean within-person percentage change in mosquito infectivity 2 days after primaquine treatment in participants who completed the study after optimisation of the infectivity assay, had both a pre-treatment infectivity measurement and at least one follow-up infectivity measurement, and who were given the correct primaquine dose. The safety endpoint was the mean within-person change in haemoglobin concentration during 28 days of study follow-up in participants with at least one follow-up visit. This study is registered with ClinicalTrials.gov, number NCT01743820. FINDINGS: Between Jan 2, 2013, and Nov 27, 2014, we enrolled 81 participants. In the primary analysis sample (n=71), participants in the 0·25 mg/kg primaquine dose group (n=15) and 0·5 mg/kg primaquine dose group (n=14) had significantly lower mean within-person reductions in infectivity at day 2-92·6% (95% CI 78·3-100; p=0·0014) for the 0·25 mg/kg group; and 75·0% (45·7-100; p=0·014) for the 0·5 mg/kg primaquine group-compared with those in the control group (n=14; 11·3% [-27·4 to 50·0]). Reductions were not significantly different from control for participants assigned to the 0·0625 mg/kg dose group (n=16; 41·9% [1·4-82·5]; p=0·16) and the 0·125 mg/kg dose group (n=12; 54·9% [13·4-96·3]; p=0·096). No clinically meaningful or statistically significant drops in haemoglobin were recorded in any individual in the haemoglobin analysis (n=70) during follow-up. No serious adverse events were reported and adverse events did not differ between treatment groups. INTERPRETATION: A single dose of 0·25 mg/kg primaquine, given alongside dihydroartemisinin-piperaquine, was safe and efficacious for the prevention of P falciparum malaria transmission in boys and men who are not deficient in G6PD. Future studies should assess the safety of single-dose primaquine in G6PD-deficient individuals to define the therapeutic range of primaquine to enable the safe roll-out of community interventions with primaquine. FUNDING: Bill & Melinda Gates Foundation.

BACKGROUND AND AIMS: Gallstone disease (GSD) associates with significant morbidity and mortality. Decreased secretion of bile acids has been suggested as a driving factor for GSD. Recently, we linked the protein phosphatase 1 regulatory subunit 3 beta (PPP1R3B) rs4240624 genotype to decreased bile acid levels in bile. In this study, we investigated whether these individuals had an increased risk for GSD as well as the differences in the lipid composition of the gallbladder bile of these individuals compared to controls and patients with GSD. METHODS: Bile acids, cholesterol, and phospholipid levels in gallbladder bile samples were enzymatically measured in 46 patients (34 female, age 45.7 ± 9.8 years, BMI 41.3 ± 4.4 kg/m2) who underwent elective laparoscopic Roux-en-Y gastric bypass. The lipidome of gallbladder bile was analyzed using high-performance liquid chromatography-mass spectrometry. Gallstone status was evaluated using abdominal ultrasonography before the surgery. RESULTS: The G allele of PPP1R3B rs4240624 was significantly associated with GSD in patients with obesity. We validated this association in the UK Biobank. Bile lipidomics demonstrated that 13 of the 17 minor lipid classes measured were higher in individuals with the G allele. The concentrations of bile acids, cholesterol, and phospholipids, as well as the cholesterol saturation index, were lower in patients with GSD than in those without gallstones. GSD had an effect similar to that of PPP1R3B genotype on minor lipids. CONCLUSION: The PPP1R3B rs4240624 genotype is associated with gallstones and with changes in gallbladder bile similar to those observed in patients with gallstones, suggesting that the PPP1R3B genotype contributes to the risk of gallstones by altering the bile lipidome.

Statins reduce cholesterol, prevent cardiovascular disease, and are among the most commonly prescribed medications in the world. Statin-associated musculoskeletal symptoms (SAMS) impact statin adherence and ultimately can impede the long-term effectiveness of statin therapy. There are several identified pharmacogenetic variants that impact statin disposition and adverse events during statin therapy. SLCO1B1 encodes a transporter (SLCO1B1; alternative names include OATP1B1 or OATP-C) that facilitates the hepatic uptake of all statins. ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin. CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins. Genetic variation in each of these genes alters systemic exposure to statins (i.e., simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin), which can increase the risk for SAMS. We summarize the literature supporting these associations and provide therapeutic recommendations for statins based on SLCO1B1, ABCG2, and CYP2C9 genotype with the goal of improving the overall safety, adherence, and effectiveness of statin therapy. This document replaces the 2012 and 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for SLCO1B1 and simvastatin-induced myopathy.