Sludge filterability in membrane bioreactors (MBRs) fluctuates and affects membrane fouling. Therefore, understanding the reasons for the fluctuations of sludge filterability is important for the ...efficient operation of MBRs. In this study, a pilot-scale MBR treating municipal wastewater was operated for about 600 days and the variations in sludge filterability were continuously monitored by batch-filtration experiments using the same membranes as in the MBR. To investigate the reasons for the deterioration of sludge filterability, constituents in sludge supernatant were intensively monitored, and the correlations with sludge filterability were determined. The concentration of lipopolysaccharides (LPS) in sludge supernatant exhibited significantly higher correlation with sludge filterability than did conventional indexes (i.e. polysaccharides and proteins). Size fractions affecting MBR sludge filterability were also investigated, and it was suggested that colloidal LPS deteriorated MBR sludge filterability. Based on the long-term operation of the MBR, increase in colloidal LPS under low temperatures of the mixed liquor suspension was a key factor in the deterioration of sludge filterability. The impact of LPS increasing under low temperatures should be investigated by operating bench-scale MBRs fed with synthetic wastewater in controlled conditions.
This paper reviews the function of the mitochondria and the mechanisms by which nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) cause mitochondrial toxicity.
Highly active ...antiretroviral therapy (HAART) reduces rates of morbidity and mortality due to HIV disease. However, long-term treatment with these drugs may be associated with adverse effects. Nucleoside and nucleotide analogues are potent inhibitors of HIV reverse transcriptase and have become the cornerstone of HAART. Unfortunately, these drugs have also been shown to inhibit cellular polymerases, most notably mitochondrial DNA polymerase γ.
Studies of the NRTIs in enzyme assays and cell cultures demonstrate the following hierarchy of mitochondrial DNA polymerase γ inhibition: zalcitabine ≥ didanosine ≥ stavudine > lamivudine > zidovudine > abacavir. In vitro investigations have also documented impairment of the mitochondrial enzymes adenylate kinase and the adenosine diphosphate/adenosine triphosphate translocator. Inhibition of DNA polymerase γ and other mitochondrial enzymes can gradually lead to mitochondrial dysfunction and cellular toxicity. The clinical manifestations of NRTI-induced mitochondrial toxicity resemble those of inherited mitochondrial diseases (ie, hepatic steatosis, lactic acidosis, myopathy, nephrotoxicity, peripheral neuropathy, and pancreatitis). Fat redistribution syndrome, or HIV-associated lipodystrophy, is another side effect attributed in part to NRTI therapy. The morphologic and metabolic complications of this syndrome are similar to those of the mitochondrial disorder known as multiple symmetric lipomatosis, suggesting that this too may be related to mitochondrial toxicity. The pathophysiology of less common adverse effects of nucleoside analogue therapy, such as diabetes, ototoxicity, and retinal lesions, may be related to mitochondrial dysfunction but have not been adequately studied.
NRTIs can block both HIV reverse transcriptase and mitochondrial DNA polymerase γ. Inhibition of the latter enzyme is the most likely cause of the adverse effects associated with these drugs.
Clinical samples from 123 foals with suspected rhodococcosis submitted to the Veterinary Microbiological Diagnostic Centre of the Faculty of Veterinary Medicine between 1993 and 2006 were tested for ...the presence of the virulence gene vapA. Of the 123 samples, 120 were vapA‐positive and 3 vapA‐negative Rhodococcus equi were isolated. The 120 vapA‐positive R. equi were isolated from 70 tracheal wash, 19 lung tissues, 7 lymph nodes, 6 synovial fluids, 13 abscesses or pus and single isolates from the uterus, gut, cerebrospinal fluid, abdomen fluid and faeces. Of the 120 isolates, 46 were from Dutch warmblood horses, 23 from Friesian horses, 14 from Trotters, 4 from Holsteiners, 3 from Arab breed, 2 from ponies, 1 from a Welsh pony and 27 from undefined breed horses. Using plasmid profile analysis of the 120 isolates, 117 isolates contained the 85‐kb type I plasmid, 2 contained the 87‐kb type I plasmid and 1 contained the novel 52‐kb non‐mobilizable virulence plasmid reported recently. These results showed that the virulent R. equi strains harbouring a virulence plasmid of 85‐kb type I or 87‐kb type I, which have been detected in clinical isolates from five European countries, are widespread in the Netherlands. This is the first report of plasmid types of clinical R. equi isolates in the Netherlands.
Significance and Impact of the Study: Rhodococcus equi is a bacterial pathogen well‐known to cause pyogranulomatous pneumonia and lung abscesses in foals aged less than 6 months. This study showed that the virulent R. equi strains harbouring a virulence plasmid of 85‐kb type I or 87‐kb type I, which have been detected in clinical isolates from five European countries, are widespread in the Netherlands, and a new variant of pVAPA 52 kb was identified. This is the first report of plasmid types of clinical R. equi isolates in the Netherlands.
Rhodococcus equi was isolated from the gastrointestinal contents of earthworms (family Megascolecidae) and their surrounding soil collected from pastures of two horse‐breeding farms in Aomori ...Prefecture, outdoor pig pens, forest in Towada campus, orange groves and forest where wild boars (Sus scrofa) are established in Tanabe, Wakayama Prefecture. The number of R. equi in the lower gastrointestinal contents of 23 earthworms collected from our campus was significantly larger than that of the upper gastrointestinal content. The mean numbers of R. equi from the gastrointestinal contents of earthworms collected from the various places were 2·3‐fold to 39·7‐fold more than those of the surrounding soil samples. In all, 1771 isolates from the earthworms and 489 isolates from the soil samples were tested for the presence of vapA and vapB genes using polymerase chain reaction. At the horse‐breeding farm N, 9 of the 109 isolates (8·3%) from the earthworms and 7 of the 106 isolates (6·6%) from the soil samples were positive for the vapA gene. At the University’s forest, one of the 250 isolates (0·4%) from the gastrointestinal contents of the earthworm was positive for the vapB gene. These results revealed that R. equi can be found in significant quantities in the gastrointestinal contents of earthworms, suggesting that they act as an accumulator of R. equi in the soil environment and as a source or reservoir of animal infection.
Significance and Impact of the Study: Rhodococcus equi is Gram‐positive, soil‐dwelling pathogenic bacteria that cause pulmonary and extra pulmonary pyogranulomatous infections in various animal species and humans. This study showed that R. equi can be found in significant quantities in the gastrointestinal contents of earthworms, suggesting that they act as an accumulator of R. equi in the soil environment and as a source or reservoir of animal infection.
Rhodococcus equi emerged as a zoonotic pathogen of human immunodeficiency virus‐infected patients over the last three decades. Two virulence plasmid types of R. equi, pVAPA and pVAPB associated with ...equine and porcine isolates, have been recognized, and more recently, pVAPN, a novel host‐associated virulence plasmid in R. equi, was found in bovine and caprine isolates. We reinvestigated 39 previously reported isolates of R. equi from patients with and without acquired immunodeficiency syndrome (AIDS) by detecting vapA, vapB and vapN using PCR and plasmid profiling. After excluding one isolate that could not be cultured from frozen storage, eight isolates carried a virulence plasmid encoding vapA (pVAPA), 10 carried a virulence plasmid encoding vapB (pVAPB), seven carried a virulence plasmid encoding vapN (pVAPN) and 13 were negative for those genes. Of the 29 isolates from patients with AIDS, 7, 10 and 5 harboured pVAPA, pVAPB and pVAPN respectively. Among nine isolates from patients without AIDS, one and two harboured pVAPA and pVAPN respectively. This study demonstrated that pVAPN‐positive R. equi existed in human isolates before 1994 and reaffirmed that equine‐associated pVAPA‐positive, porcine‐associated pVAPB‐positive and bovine‐ or caprine‐associated pVAPN‐positive R. equi are widely spread globally. Because domestic animals might be major sources of human infection, further research is needed to reveal the prevalence of pVAPN‐positive R. equi infection in cattle and goats.
Significance and Impact of the Study: Rhodococcus equi is a pathogenic cause of zoonotic diseases with a broad host range. This study demonstrated that virulence R. equi existed in human isolates before 1994 and reaffirmed that equine‐associated pVAPA‐positive, porcine‐associated pVAPB‐positive and bovine‐ or caprine‐associated pVAPN‐positive R. equi are widely spread globally. This study adds important information that domestic animals are major sources of human infection, thus adversely affecting public health.
Objectives
HIV antiretroviral therapy during pregnancy is recommended to reduce the risk of mother‐to‐child transmission and for maternal care. Physiological changes during pregnancy can affect ...pharmacokinetics. The impact of pregnancy was evaluated for once‐daily (qd) darunavir/ritonavir.
Methods
HIV‐1–infected pregnant women on an antiretroviral regimen that includes darunavir were enrolled in the study and further treated with darunavir/ritonavir 800/100 mg qd. Plasma concentrations were assessed over 24 h during the second and third trimesters and postpartum using a validated high‐performance liquid chromatography tandem mass spectrometry assay for total darunavir and ritonavir, and using 14C‐darunavir–fortified plasma for unbound darunavir. Pharmacokinetic parameters were derived using noncompartmental analysis. Safety and antiviral response were assessed at all visits.
Results
Data were available for 16 women. The area under the plasma concentration–time curve from 0 to 24 h (AUC24h) for total darunavir was 34–35% lower during pregnancy vs. postpartum. Unbound darunavir AUC24h was 20–24% lower during pregnancy vs. postpartum. The minimum plasma concentration of total and unbound darunavir was 32–50% and 13–38% lower, respectively, during pregnancy vs. postpartum. The antiviral response (< 50 HIV‐1 RNA copies/mL) was 59% at baseline and increased to 87–100% during the trial; the CD4 count increased over time. One serious adverse event (gestational diabetes) was judged as possibly related to study medication. All 16 infants born to women remaining in the study at delivery were HIV‐1 negative (two were premature).
Conclusions
Total darunavir exposure decreased during pregnancy, but the decrease was less for unbound (active) darunavir. These changes are not considered clinically relevant. Darunavir/ritonavir 800/100 mg qd may therefore be a treatment option for HIV‐1–infected pregnant women.
Objectives
Etravirine is a substrate and inducer of cytochrome P450 (CYP) 3A and a substrate and inhibitor of CYP2C9 and CYPC2C19. Darunavir/ritonavir is a substrate and inhibitor of CYP3A. ...Artemether and lumefantrine are primarily metabolized by CYP3A; artemether is also metabolized to a lesser extent by CYP2B6, CYP2C9 and CYP2C19. Artemether has an active metabolite, dihydroartemisinin. The objective was to investigate pharmacokinetic interactions between darunavir/ritonavir or etravirine and arthemether/lumefrantrine.
Methods
This single‐centre, randomized, two‐way, two‐period cross‐over study included 33 healthy volunteers. In panel 1, 17 healthy volunteers received two treatments (A and B) in random order, with a washout period of 4 weeks between treatments: treatment A: artemether/lumefantrine 80/480 mg alone, in a 3‐day course; treatment B: etravirine 200 mg twice a day (bid) for 21 days with artemether/lumefantrine 80/480 mg from day 8 (a 3‐day treatment course). In panel 2, another 16 healthy volunteers received two treatments, similar to those in panel 1 but instead of etravirine, darunavir/ritonavir 600/100 mg bid was given.
Results
Overall, 28 of the 33 volunteers completed the study. Co‐administration of etravirine reduced the area under the plasma concentration–time curve (AUC) of artemether by 38%; 90% confidence interval (CI) 0.48–0.80, dihydroartemisinin (by 15%; 90% CI 0.75–0.97) and lumefantrine (by 13%; 90% CI 0.77–0.98) at steady state. Co‐administration of darunavir/ritonavir reduced the AUC of artemether (by 16%; 90% CI 0.69–1.02) and dihydroartemisinin (by 18%; 90% CI 0.74–0.91) but increased lumefantrine (2.75‐fold; 90% CI 2.46–3.08) at steady state. Co‐administration of artemether/lumefantrine had no effect on etravirine, darunavir or ritonavir AUC. No drug‐related serious adverse events were reported during the study.
Conclusions
Co‐administration of etravirine with artemether/lumefantrine may lower the antimalarial activity of artemether and should therefore be used with caution. Darunavir/ritonavir can be co‐administered with artemether/lumefantrine without dose adjustment but should be used with caution.
Summary
Approximately three million individuals in the United States are chronically infected with hepatitis C virus (HCV). Chronic HCV infection may lead to the development of compensated as well as ...decompensated liver cirrhosis. The Phase II IMPACT study was conducted in HCV genotype 1‐ or 4‐infected cirrhotic patients with portal hypertension or decompensated liver disease and assessed for the first time the combination of the three direct‐acting antivirals simeprevir, daclatasvir and sofosbuvir. Treatment‐naïve or treatment‐experienced adults with Child‐Pugh (CP) score <7 (CP A) and evidence of portal hypertension, or CP score 7–9 (CP B), received 12 weeks of simeprevir 150 mg, daclatasvir 60 mg and sofosbuvir 400 mg, once daily. The primary efficacy endpoint was sustained virologic response 12 weeks after end of treatment (SVR12). Pharmacokinetics and safety were also assessed. Overall, 40 patients were enrolled (CP A: 19; CP B: 21). All 40 patients achieved SVR12. At week 8, the mean pharmacokinetic exposure to simeprevir, sofosbuvir, daclatasvir and GS‐331007 (sofosbuvir metabolite) was 2.2‐, 1.5‐, 1.2‐ and 1.2‐fold higher in patients with CP B than CP A, respectively. Grade 1/2 adverse events (AEs) occurred in 26 of 40 (65%) patients. One CP B patient had a Grade 3 AE (gastrointestinal haemorrhage), which was reported as a serious AE but not considered related to study drugs. Treatment for 12 weeks with simeprevir, daclatasvir and sofosbuvir was generally safe and well tolerated, and resulted in 100% of cirrhotic patients with portal hypertension or decompensated liver disease achieving SVR12.
Summary
The phase 2, open‐label ACCORDION (ClinicalTrials.gov: NCT02349048) study investigated the efficacy, safety and pharmacokinetics of a 6‐ or 8‐week regimen of simeprevir, daclatasvir and ...sofosbuvir in treatment‐naïve patients with chronic hepatitis C virus (HCV) genotype (GT) 1 infection and either early‐stage fibrosis or compensated cirrhosis. Patients were assigned to treatment groups according to their fibrosis stage. Early‐stage fibrosis: simeprevir 150 mg, daclatasvir 60 mg, sofosbuvir 400 mg once daily for 6 weeks; compensated cirrhosis: same regimen for 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety, tolerability and pharmacokinetics of simeprevir, daclatasvir and sofosbuvir were investigated. Sixty‐eight patients were treated (6‐week group: n = 59; 8‐week group: n = 9). SVR12 was achieved by 86.4% (51/59) of patients with early‐stage fibrosis and by 100% (9/9) of patients with cirrhosis. The main reason for not achieving SVR12 in the 6‐week group was viral relapse (11.9%; 7/59). One patient had on‐treatment failure due to an early withdrawal (lost to follow‐up due to incarceration). One patient with SVR12 in the 6‐week group had a late viral relapse at post‐treatment week 24. No clinically significant drug‐drug interactions were observed. Adverse events were reported in 63.2% of patients (43/68) and were mainly grade 1/2. None of these led to treatment discontinuation. The 3 direct‐acting antiviral regimens of simeprevir, daclatasvir and sofosbuvir were safe and well tolerated in treatment‐naïve, HCV GT1‐infected patients with early‐stage fibrosis or compensated cirrhosis.
The pharmacokinetics and pharmacodynamics of the antiretroviral agent etravirine were evaluated in two phase III clinical trials. Pharmacokinetic data were available in 577 patients randomized to ...receive etravirine. The mean (SD) population‐pharmacokinetics‐derived area under the concentration–time curve at 12 h (AUC12 h) and concentration at 0 h (C0 h) were 5,501 (4,544) ng·h/ml and 393 (378) ng/ml, respectively. Hepatitis C coinfection raised etravarine exposure, and concomitant use of tenofovir disoproxil fumarate lowered etravirine exposure, but these changes were not considered clinically relevant. Etravirine apparent oral clearance was not affected by age, weight, sex, race, hepatitis B coinfection status, creatinine clearance, or concomitant use of enfuvirtide. Virologic response (<50 copies/ml) at week 24 was 59% in patients randomized to etravirine vs. 41% in those receiving placebo (P < 0.0001). There was no apparent relationship between etravirine pharmacokinetics and either efficacy or safety. Factors other than the pharmacokinetics of etravirine such as the characteristics of the patients and the disease, as well as characteristics of the treatment regimen, predict virologic response.
Clinical Pharmacology & Therapeutics (2010) 88 5, 695–703. doi: 10.1038/clpt.2010.181
PDF
