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It is urgent to develop new antimalarial drugs with good therapeutic effects to address the emergence of drug resistance. Here, the artelinic acid-choline derivative (AD) was synthesized by dehydration reaction and esterification reaction, aimed to avoid the emergence of drug resistance by synergistic effect of artemisinins and choline derivative, which could compete with choline for rate-limiting enzymes in the phosphatidylcholine (PC) biosynthetic pathway. AD was formulated into liposomes (ADLs) by the thin-film hydration method. Efficacy of ADLs was evaluated by Peters 4-day suppression test. The suppression percentage against Plasmodium yoelii BY265 (PyBY265) in ADLs group was higher than those of positive control groups (dihydroartemisinin liposomes, P < 0.05) and other control groups (P ⩽ 0.05) at the doses of 4.4, 8.8, 17.6 µmol (kg·d)−1, respectively. The negative conversion fraction, recrudescence fraction and survival fraction of ADLs group were superior to other control groups. Pharmacokinetics in rats after intravenous injection suggested that ADLs exhibited higher exposure levels (indexed by area under concentration-time curve) than that of AD solution, artelinic acid liposomes or artelinic acid solution (P < 0.01). Taken together, ADLs exhibited promising antimalarial efficacy and pharmacokinetic characteristics.
On many Australian commercial pig farms, groups of growing pigs are mass-medicated through their drinking water with selected antimicrobials for short periods to manage herd health. However, delivery of medication in drinking water cannot be assumed to deliver an equal dose to all animals in a group. There is substantial between-animal variability in systemic exposure to an antimicrobial (i.e. the antimicrobial concentration in plasma), resulting in under-dosing or over-dosing of many pigs. Three sources of this between-animal variability during a water medication dosing event are differences in: (1) concentration of the active constituent of the antimicrobial product in water available to pigs at drinking appliances in each pen over time, (2) medicated water consumption patterns of pigs in each pen over time, and (3) pharmacokinetics (i.e. oral bioavailability, volume of distribution and clearance between pigs and within pigs over time). It is essential that factors operating on each farm that influence the range of systemic exposures of pigs to an antimicrobial are factored into antimicrobial administration regimens to reduce under-dosing and over-dosing.
The ventricular assist device is being increasingly used as a “bridge-to-transplant” option in children with heart failure who have failed medical management. Care for this medically complex population must be optimised, including through concomitant pharmacotherapy. Pharmacokinetic/pharmacodynamic alterations affecting pharmacotherapy are increasingly discovered in children supported with extracorporeal membrane oxygenation, another form of mechanical circulatory support. Similarities between extracorporeal membrane oxygenation and ventricular assist devices support the hypothesis that similar alterations may exist in ventricular assist device-supported patients. We conducted a literature review to assess the current data available on pharmacokinetics/pharmacodynamics in children with ventricular assist devices. We found two adult and no paediatric pharmacokinetic/pharmacodynamic studies in ventricular assist device-supported patients. While mechanisms may be partially extrapolated from children supported with extracorporeal membrane oxygenation, dedicated investigation of the paediatric ventricular assist device population is crucial given the inherent differences between the two forms of mechanical circulatory support, and pathophysiology that is unique to these patients. Commonly used drugs such as anticoagulants and antibiotics have narrow therapeutic windows with devastating consequences if under-dosed or over-dosed. Clinical studies are urgently needed to improve outcomes and maximise the potential of ventricular assist devices in this vulnerable population.
New drugs and treatments for diseases caused by intracellular pathogens, such as leishmaniasis and the Leishmania species, have proved to be some of the most difficult to discover and develop. The focus of discovery research has been on the identification of potent and selective compounds that inhibit target enzymes (or other essential molecules) or are active against the causative pathogen in phenotypic in vitro assays. Although these discovery paradigms remain an essential part of the early stages of the drug R & D pathway, over the past two decades additional emphasis has been given to the challenges needed to ensure that the potential anti-infective drugs distribute to infected tissues, reach the target pathogen within the host cell and exert the appropriate pharmacodynamic effect at these sites. This review will focus on how these challenges are being met in relation to Leishmania and the leishmaniases with lessons learned from drug R & D for other intracellular pathogens.
Antimicrobials are among the most prescribed drugs and their prescription increases with age, due to frailty and accrued risk factors for acquiring infections. Antimicrobial prescription in elderly patients must not only account for the risk of toxicity due to drug overexposure, but also of treatment failure or promotion of antimicrobial resistance due to under-dosage. This paper reviews the main antimicrobial, pharmacokinetic and pharmacodynamic variations induced by aging, comorbidities and polypharmacy, and how to take them into account to optimize antimicrobial prescription in elders.
Arginine (ARG) and its precursor citrulline (CIT) are popular dietary supplements, especially for the elderly. However, age-related reductions in lean body mass and alterations in organ functions could change their bioavailability. Pharmacokinetics and tolerance to amino acid (AA) loads are poorly documented in elderly subjects. The objective here was to characterise the plasma kinetics of CIT and ARG in a single-dosing study design. Eight fasting elderly men underwent two separate isomolar oral loading tests (10 g of CIT or 9·94 g of ARG). Blood was withdrawn over an 8-h period to measure plasma AA concentrations. Only CIT, ornithine and ARG plasma concentrations were changed. Volume of distribution was not dependent on AA administered. Conversely, parameters related to ARG kinetics were strongly dependent on AA administered: after ARG load, elimination was higher (ARG>CIT; P=0·041) and admission period+time at peak concentration was lower (ARG<CIT; P=0·033), and the combination of both phenomena results in a marked increase in ARG availability when CIT was administered (ARG<CIT; P=0·033) compared with ARG administration itself. In conclusion, a single CIT administration in the elderly is safe and well tolerated, and CIT proves to be a better in vivo ARG precursor than ARG itself in healthy elderly subjects.
In recent decades, in silico absorption, distribution, metabolism, excretion (ADME), and toxicity (T) modelling as a tool for rational drug design has received considerable attention from pharmaceutical scientists, and various ADME/T-related prediction models have been reported. The high-throughput and low-cost nature of these models permits a more streamlined drug development process in which the identification of hits or their structural optimization can be guided based on a parallel investigation of bioavailability and safety, along with activity. However, the effectiveness of these tools is highly dependent on their capacity to cope with needs at different stages, e.g. their use in candidate selection has been limited due to their lack of the required predictability. For some events or endpoints involving more complex mechanisms, the current in silico approaches still need further improvement. In this review, we will briefly introduce the development of in silico models for some physicochemical parameters, ADME properties and toxicity evaluation, with an emphasis on the modelling approaches thereof, their application in drug discovery, and the potential merits or deficiencies of these models. Finally, the outlook for future ADME/T modelling based on big data analysis and systems sciences will be discussed.
Sildenafil is frequently prescribed to children with single ventricle heart defects. These children have unique hepatic physiology with elevated hepatic pressures, which may alter drug pharmacokinetics. We sought to determine the impact of hepatic pressure on sildenafil pharmacokinetics in children with single ventricle heart defects.
A population pharmacokinetic model was developed using data from 20 single ventricle children receiving single-dose intravenous sildenafil during cardiac catheterisation. Non-linear mixed effect modelling was used for model development, and covariate effects were evaluated based on estimated precision and clinical significance.
The analysis included a median (range) of 4 (2–5) pharmacokinetic samples per child. The final structural model was a two-compartment model for sildenafil with a one-compartment model for des-methyl-sildenafil (active metabolite), with assumed 100% sildenafil to des-methyl-sildenafil conversion. Sildenafil clearance was unaffected by hepatic pressure (clearance=0.62 L/hour/kg); however, clearance of des-methyl-sildenafil (1.94×(hepatic pressure/9)−1.33 L/hour/kg) was predicted to decrease ~7-fold as hepatic pressure increased from 4 to 18 mmHg. Predicted drug exposure was increased by ~1.5-fold in subjects with hepatic pressures ⩾10 versus <10 mmHg (median area under the curve=533 versus 792 µg*h/L).
Elevated hepatic pressure delays clearance of the sildenafil metabolite – des-methyl-sildenafil – and increases drug exposure. We speculate that this results from impaired biliary clearance. Hepatic pressure should be considered when prescribing sildenafil to children. These data demonstrate the importance of pharmacokinetic assessments in patients with unique cardiovascular physiology that may affect drug metabolism.
Vitamin E (α-, β-, γ- and δ-tocopherol and -tocotrienol) is an essential factor in the human diet and regularly taken as a dietary supplement by many people, who act under the assumption that it may be good for their health and can do no harm. With the publication of meta-analyses reporting increased mortality in persons taking vitamin E supplements, the safety of the micronutrient was questioned and interactions with prescription drugs were suggested as one potentially underlying mechanism. Here, we review the evidence in the scientific literature for adverse vitamin E–drug interactions and discuss the potential of each of the eight vitamin E congeners to alter the activity of drugs. In summary, there is no evidence from animal models or randomised controlled human trials to suggest that the intake of tocopherols and tocotrienols at nutritionally relevant doses may cause adverse nutrient–drug interactions. Consumption of high-dose vitamin E supplements ( ≥ 300 mg/d), however, may lead to interactions with the drugs aspirin, warfarin, tamoxifen and cyclosporine A that may alter their activities. For the majority of drugs, however, interactions with vitamin E, even at high doses, have not been observed and are thus unlikely.
Older people are high consumers of prescription drugs and are at increasing risk of polypharmacy and adverse reactions. Pharmacokinetic and pharmacodynamic modifications due to age and co-morbidities are an important consideration, but pharmacological background evidence to guide safe and effective therapeutic approaches are often inadequate since the older population is under-represented in clinical trials. We review the pharmacokinetic and pharmacodynamic changes that are characteristic in old age and consider evidence regarding potentially safer prescription and monitoring of drugs commonly used in older patients. We also introduce the possible role of pharmacogenomics and therapeutic drug monitoring as tools to guide the individualization of drug therapy.
The need for new drugs to treat microbial infections is pressing. The great progress made in the middle part of the twentieth Century was followed by a period of relative inactivity as the medical needs relating to infectious disease in the wealthier nations receded. Growing realisation that anti-infectives are needed in many parts of the world, to treat neglected diseases as well as to combat the burgeoning risk of resistance to existing drugs, has galvanised a new wave of research into anti-microbial drugs. The transfer of knowledge from the Pharmaceutical industry relating to the importance of understanding how to target drugs successfully within the body, and improved understanding of how pathogens interact with their hosts, is driving a series of new paradigms in anti-infective drug design. Here we provide an overview of those processes as an introduction to a series of articles from experts in this area that emerged from a meeting entitled “Emerging Paradigms in Anti-Infective Drug Design” held in London on the 17th and 18th September 2012. The symposium was organised jointly by British Society for Parasitology (BSP) and the Biological & Medicinal Chemistry sector of the Royal Society of Chemistry (RSC) and held at the London School of Hygiene & Tropical Medicine. The symposium set out to cover all aspects of the identification of new therapeutic modalities for the treatment of neglected and tropical diseases. We aimed to bring together leading scientists from all the disciplines working in this field and cover the pharmacology, medicinal chemistry and drug delivery of potential new medicines. Sessions were held on: “Target diseases and targets for drugs”, “Target based medicinal chemistry”, “Bioavailability and chemistry”, “Targeting intracellular microbes”, “Alternative approaches and models”, and “New anti-infectives – how do we get there?”
This symposium was organised by Simon Croft (LSHTM) and Mike Barrett (University of Glasgow) for the BSP, and David Alker (David Alker Associates) and Andrew Stachulski (University of Liverpool) for the Biological & Medicinal Chemistry sector of the RSC.
Pregnancy is a state of flux with the placental-fetal unit undergoing constant changes that affect both pharmacodynamics and pharmacokinetics of many drugs. Pregnancy affects hepatic biotransformation in an enzyme-specific manner. Increased cardiac output, tissue flow, and vasodilatation during pregnancy may enhance absorption of drugs administered subcutaneously, intramuscularly, epidurally, transvaginally, and via mucous membranes. The treatment of drug overdose in pregnancy presents a unique challenge because of changes in the pharmacodynamics and pharmacokinetics of drugs during gravid state. The most frequently used agents for self-inflicted poisoning during pregnancy are analgesics, antipyretics, and antirheumatics. The treatment of acetaminophen overdose is aimed at decreasing the absorption of acetaminophen and protecting the hepatocytes from the toxic effects of the highly reactive metabolites. The therapeutic approach in carbon monoxide poisoning is to deliver high-dose oxygen to displace carbon monoxide from the hemoglobin molecule.
To investigate the feasibility of postauricular hypodermic injection for treating inner ear disorders, we compared perilymph pharmacokinetics for postauricular versus intravenous injection, using magnetic resonance imaging, in an animal model.
Twelve albino guinea pigs were divided randomly into two groups and administered gadopentetate dimeglumine via either a postauricular or an intravenous bolus injection. A 7.0 Tesla magnetic resonance imaging system was used to assess the signal intensities of gadolinium-enhanced images of the cochlea, as a biomarker for changes in gadopentetate dimeglumine concentration in the perilymph. Pharmacokinetic parameters were calculated based on these signal intensity values.
Guinea pigs receiving postauricular injection showed longer times to peak signal intensity, longer elimination half-life, longer mean residence time and a greater area under the signal–time curve (from pre-injection to the last time point) (p < 0.05).
Postauricular injection shows potential as an efficient drug delivery route for the treatment of inner ear disorders.
CNS drug development is rapidly evolving to meet the unique and changing demands of the fields of psychiatry and neurology. Phase I studies are traditionally focused on determining the safety, tolerability, and pharmacokinetics of a new molecular entity in young healthy volunteers: first in a single ascending dose (SAD) study and then in a multiple ascending dose (MAD) study. The use of an adaptive design to examine data and modify the study in real time may also promote time- and cost-efficient identification of novel molecular entities (NMEs) that have the characteristics necessary to be successful in confirm stages of drug development research. This chapter discusses how use of biomarkers as surrogate endpoints can be incorporated into early clinical trials to determine if a drug modulates the appropriate targets, which enhances the likelihood of demonstrating efficacy in the confirm phase of clinical testing.
The pharmacokinetics of a single I.V dose of natalizumab were studied in a phase 1, dose-escalation study in 28 multiple sclerosis (MS) patients. As part of the clinical trial program to establish the pharmacokinetic/pharmacodynamic and safety profiles of natalizumab, four Phase 1, dose-finding studies were conducted. An additional Phase 2 study was conducted to evaluate the safety and efficacy of natalizumab in combination with glatiramer acetate (GA). One of the recommendations of the therapeutics and technology assessment subcommittee of the AAN about the use of natalizumab was to carefully monitor patients receiving natalizumab to establish its long-term safety i.e. the true risk of progressive multifocal leukoencephalopathy (PML). Large Phase 3 trials of natalizumab alone or in combination with interferon (IFN)β-1a show that natalizumab reduces the progression of disability, and dramatically reduces the frequency of relapses and magnetic resonance imaging (MRI) lesion formation in patients with relapsing MS.
Pharmacokinetics is an excellent way to introduce biomathematical modeling at the sophomore level. Students have the opportunity to develop a mathematical model of a biological phenomenon to which they all can relate. Exploring pharmacokinetics takes students through the necessary stages of mathematical modeling: determining the goals of the model, deciphering between the biological aspects to include in the model, defining the assumptions of the model, and finally, building, analyzing, using, and refining the model to answer questions and test hypotheses. Readily accessible data allows students to use the model to test hypotheses that are meaningful to them on an individual level. Students make interdisciplinary connections between this model and their previous personal, mathematical, and other classroom experiences. By beginning with a simple model involving the half-life of a drug, students take advantage of their mathematical abilities to explore the biology. They can then use the new knowledge gained from analyzing the simple model to create more complicated models, thus gaining mathematical and modeling maturity through improving the biological accuracy of the model. Through this experiences, students actually get to do applied mathematics, and they take ownership of the model.
Wholegrain cereals are reported to promote beneficial health effects. Wholegrain wheat and rye are almost exclusive sources of alkylresorcinols, and intact alkylresorcinols together with their plasma and urinary metabolites, 3-(3,5-dihydroxyphenyl)-1-propanoic acid (DHPPA) and 3,5-dihydroxybenzoic acid (DHBA), have been proposed as biomarkers of the intake of these foods in humans. The pharmacokinetics of alkylresorcinols and their metabolites in plasma have been determined but not that of the urinary metabolites. We aimed to characterise the urinary pharmacokinetics of alkylresorcinol metabolites in humans to evaluate their potential as biomarkers of wholegrain wheat and rye. A group of fifteen volunteers followed a low-alkylresorcinol diet for 2 d before ingesting a single dose of rye bread, containing 100 mg alkylresorcinols. Urine was collected between baseline (0 h) and 25 h after administration. Thereafter alkylresorcinol metabolites were quantified by HPLC with coulometric electrode array detection. Maximum excretion rates were observed at 5–6 h for both metabolites, DHPPA being predominant over DHBA and also possessing a greater area under the curve0–25 h. Total urinary recovery between 0 and 25 h yielded 43 % of ingested alkylresorcinols, and at 25 h significant amounts of metabolites were still retained in the body, suggesting that even a spot urine sample may be sufficient to indicate whether or not wholegrain wheat or rye is a daily dietary component. These results support the use of urinary DHPPA and DHBA as biomarkers of wholegrain wheat and rye and enable new potential for studying the association between wholegrain intake and diseases, even in the absence of dietary data.
Serotonin synthesis critically depends on plasma levels of tryptophan (TRP). Earlier studies have shown that for mood and cognitive benefits to occur, the ratio between TRP and other large neutral amino acids (LNAA) has to be increased by approximately 40 %. The present study investigated the dose-dependent effects of a TRP-rich hydrolysed protein (egg-protein hydrolysate, EPH) on the plasma TRP:LNAA. Moreover, it was investigated whether EPH could increase TRP:LNAA in the presence of 2 g of milk protein (MP). In a randomised double-blind crossover design, plasma amino acids were measured every 30 min for 3·5 h after ingestion of a drink containing either three different doses of 4, 8 and 12 g EPH containing 270, 560 or 800 mg of TRP, respectively, the combination of 4 g EPH and 2 g MP (74 mg TRP), or 4 g MP (148 mg TRP) in twenty healthy subjects with a mean age of 52 years. All three EPH doses caused significant increases of TRP:LNAA above 40 % at 30, 60 and 90 min after consumption in a dose-dependent manner. Compared with the 4 g EPH, the increase in TRP:LNAA in the 4 g EPH with 2 g MP condition was significantly lower at 60 min (63 v. 44 %, P < 0·001) and did not differ significantly at 90 min (58 v. 53 %, P>0·05). The present study showed that a low dose of 4 g EPH with even the addition of 2 g MP was sufficient to increase the ratio of TRP:LNAA above 40 %. Thus, EPH offers a viable ingredient to increase TRP availability.