393 research outputs found
Exploring tradeoffs in pleiotropy and redundancy using evolutionary computing
Evolutionary computation algorithms are increasingly being used to solve
optimization problems as they have many advantages over traditional
optimization algorithms. In this paper we use evolutionary computation to study
the trade-off between pleiotropy and redundancy in a client-server based
network. Pleiotropy is a term used to describe components that perform multiple
tasks, while redundancy refers to multiple components performing one same task.
Pleiotropy reduces cost but lacks robustness, while redundancy increases
network reliability but is more costly, as together, pleiotropy and redundancy
build flexibility and robustness into systems. Therefore it is desirable to
have a network that contains a balance between pleiotropy and redundancy. We
explore how factors such as link failure probability, repair rates, and the
size of the network influence the design choices that we explore using genetic
algorithms.Comment: 10 pages, 6 figure
The prevention and treatment of venous thromboembolism with LMWHs and new anticoagulants
As the risk factors for thrombosis are becoming better understood, so is the need for anticoagulation. The inherent difficulties with warfarin are such that a low-molecular-weight heparin (LMWH) is often the key therapeutic. However, there are several different species of LMWH available to the practitioner, which leads to the need for an objective guide. New agents are coming onto the marketplace, and these may supersede both warfarin and the heparins. The current report will review the biochemistry and pharmacology of different LWMHs and identify which are more suitable for the different presentations of venous thromboembolism. It will conclude with a brief synopsis of new agents which may supersede warfarin and heparin
Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro
ABSTRACT
Treatment of HIV-infected patients coinfected with
Mycobacterium tuberculosis
is challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and antituberculosis (anti-TB) drugs. The aim of this study was to quantify the effect of cobicistat (COBI) or ritonavir (RTV) in modulating DDIs between darunavir (DRV) and rifampin (RIF) in a human hepatocyte-based
in vitro
model. Human primary hepatocyte cultures were incubated with RIF alone or in combination with either COBI or RTV for 3 days, followed by coincubation with DRV for 1 h. The resultant DRV concentrations were quantified by high-performance liquid chromatography with UV detection, and the apparent intrinsic clearance (CL
int.app.
) of DRV was calculated. Both RTV and COBI lowered the RIF-induced increases in CL
int.app.
in a concentration-dependent manner. Linear regression analysis showed that log
10
RTV and log
10
COBI concentrations were associated with the percent inhibition of RIF-induced elevations in DRV CL
int.app.
, where Ξ² was equal to β234 (95% confidence interval [CI] = β275 to β193;
P
< 0.0001) and β73 (95% CI = β89 to β57;
P
< 0.0001), respectively. RTV was more effective in lowering 10 ΞΌM RIF-induced elevations in DRV CL
int.app.
(half-maximal [50%] inhibitory concentration [IC
50
] = 0.025 ΞΌM) than COBI (IC
50
= 0.223 ΞΌM). Incubation of either RTV or COBI in combination with RIF was sufficient to overcome RIF-induced elevations in DRV CL
int.app.
, with RTV being more potent than COBI. These data provide the first
in vitro
experimental insight into DDIs between RIF and COBI-boosted or RTV-boosted DRV and will be useful to inform physiologically based pharmacokinetic (PBPK) models to aid in optimizing dosing regimens for the treatment of patients coinfected with HIV and
M. tuberculosis
.
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Early experience of dolutegravir pharmacokinetics in pregnancy: high maternal levels and significant foetal exposure with twice-daily dosing
Perceptions of Research Bronchoscopy in Malawian Adults with Pulmonary Tuberculosis: A Cross-Sectional Study
Bronchoscopy is an established research tool in Malawi, enabling collection of pulmonary samples for immunological, pharmacological, and microbiological studies. It is, however, an invasive clinical procedure that offers no direct benefit to volunteering participants when used in a research capacity alone, and thus informed consent is essential. This study aimed to explore TB patientsβ understanding of research bronchoscopy, what would motivate them to participate in research bronchoscopy, and their concerns, in order to inform consenting processes for future clinical studies. We used a qualitative research design. Two focus group discussions were conducted with community members and TB patients to understand their perceptions of bronchoscopy. Transcripts were coded by multiple co-authors and thematic content analysis was used to analyse main findings. We found that Malawian patients with pulmonary TB were willing to participate in a study using research bronchoscopy for health assessment and access to improved healthcare. We identified information of value to potential participants when consenting to that may lessen some of the anxieties expressed by participants. Patient and public involvement is essential to improve informed consent and institutional trust
Pharmacokinetic modelling to estimate intracellular favipiravir ribofuranosyl-5 '-triphosphate exposure to support posology for SARS-CoV-2
OBJECTIVES: Favipiravir has discrepant activity against SARS-CoV-2 in vitro, concerns about teratogenicity and pill burden, and an unknown optimal dose. This analysis used available data to simulate the intracellular pharmacokinetics of the favipiravir active metabolite [favipiravir ribofuranosyl-5β²-triphosphate (FAVI-RTP)]. METHODS: Published in vitro data for intracellular production and elimination of FAVI-RTP in MadinβDarby canine kidney cells were fitted with a mathematical model describing the time course of intracellular FAVI-RTP as a function of favipiravir concentration. Parameter estimates were then combined with a published population pharmacokinetic model in Chinese patients to predict human intracellular FAVI-RTP. In vitro FAVI-RTP data were adequately described as a function of concentrations with an empirical model, noting simplification and consolidation of various processes and several assumptions. RESULTS: Parameter estimates from fittings to in vitro data predict a flatter dynamic range of peak to trough for intracellular FAVI-RTP (peak to trough ratio of βΌ1 to 1) when driven by a predicted free plasma concentration profile, compared with the plasma profile of parent favipiravir (ratio of βΌ2 to 1). This approach has important assumptions, but indicates that, despite rapid clearance of the parent from plasma, sufficient intracellular FAVI-RTP may be maintained across the dosing interval because of its long intracellular half-life. CONCLUSIONS: Population mean intracellular FAVI-RTP concentrations are estimated to be maintained above the Km for the SARS-CoV-2 polymerase for 9βdays with a 1200βmg twice-daily regimen (following a 1600βmg twice-daily loading dose on day 1). Further evaluation of favipiravir as part of antiviral combinations for SARS-CoV-2 is warranted
Genetic determinants of the pharmacokinetic variability of rifampin in Malawian adults with pulmonary tuberculosis
D.J.S. was supported by a Wellcome Trust Clinical PhD Fellowship (086757/Z/08/A to D.J.S.). A.D.M. was supported by a National Institute for Health Research Integrated Clinical Academic Training Fellowship and a Wellcome Trust Clinical PhD Fellowship (105/392/B/14/Z). The Malawi Liverpool Wellcome Trust Clinical Research Programme is supported by a strategic award from the Wellcome Trust.Variable exposure to antituberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the SLCO1B1 locus on the plasma area under the concentration-time curve (AUC) of rifampin. We evaluated the contribution of single nucleotide polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC and CES-1) to interindividual pharmacokinetic variability in Malawi. A total of 174 adults with pulmonary TB underwent sampling of plasma rifampin concentrations at 2 and 6 h postdose. Data from a prior cohort of 47 intensively sampled, similar patients from the same setting were available to support population pharmacokinetic model development in NONMEM v7.2, using a two-stage strategy to improve information during the absorption phase. In contrast to recent studies in South Africa and Uganda, SNPs in SLCO1B1 did not explain variability in AUC0-β of rifampin. No pharmacokinetic associations were identified with AADAC or CES-1 SNPs, which were rare in the Malawian population. Pharmacogenetic determinants of rifampin exposure may vary between African populations. SLCO1B1 and other novel candidate genes, as well as nongenetic sources of interindividual variability, should be further explored in geographically diverse, adequately powered cohorts.Publisher PDFPeer reviewe
Muscle atrophy and metal-on-metal hip implants
Background and purpose β Muscle atrophy is seen in patients with metal-on-metal (MOM) hip implants, probably because of inflammatory destruction of the musculo-tendon junction. However, like pseudotumors, it is unclear when atrophy occurs and whether it progresses with time. Our objective was to determine whether muscle atrophy associated with MOM hip implants progresses with time.
Patients and methods β We retrospectively reviewed 74 hips in 56 patients (32 of them women) using serial MRI. Median age was 59 (23β83) years. The median time post-implantation was 83 (35β142) months, and the median interval between scans was 11 months. Hip muscles were scored using the Pfirrmann system. The mean scores for muscle atrophy were compared between the first and second MRI scans. Blood cobalt and chromium concentrations were determined.
Results β The median blood cobalt was 6.84 (0.24β90) ppb and median chromium level was 4.42 (0.20β45) ppb. The median Oxford hip score was 34 (5β48). The change in the gluteus minimus mean atrophy score between first and second MRI was 0.12 (p = 0.002). Mean change in the gluteus medius posterior portion (unaffected by surgical approach) was 0.08 (p = 0.01) and mean change in the inferior portion was 0.10 (p = 0.05). Mean pseudotumor grade increased by 0.18 (p = 0.02).
Interpretation β Worsening muscle atrophy and worsening pseudotumor grade occur over a 1-year period in a substantial proportion of patients with MOM hip implants. Serial MRI helps to identify those patients who are at risk of developing worsening soft-tissue pathology. These patients should be considered for revision surgery before irreversible muscle destruction occurs
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