Pharmacokinetic Pharmacodynamic Properties Research Articles

The Dawning Era of Anticancer Nanomedicines: From First Principles to Application of Silk Nanoparticles

AbstractThis review introduces nanomedicines and medical silks by addressing seminal and recent research within these fields. First, the successes of nanoparticles in improving the safety profiles and pharmacokinetic–pharmacodynamic properties are explored but also the concepts of threshold dosing and targeting of tumor‐associated macrophages. Current barriers to systemic delivery of nanomedicines are detailed and methods to overcome these barriers and increase tumor targeting are evaluated, namely: tuning the nanomedicine size and surface charge for enhanced tumor accumulation and penetration; non‐spherical nanomedicine morphologies for macrophage evasion and targeted delivery to endothelial cells; and, surface functionalization for stealth coatings and targeting receptor‐mediated endocytosis. The advantages of using silk as a nanomedicine with reference to its structure, composition, biological performance, and formulation are discussed. While batch methods for silk processing enable the formation of nano to microparticles, continuous technology can overcome bottlenecks of the deployed engineering methods such as low throughput and poor reproducibility. Finally, the chemical modification of silk using homogeneous and heterogenous chemistries is assessed within the nanomedicine context. Overall, this review covers silk nanomedicines from first principles to carrier design and on to areas of future development.

Phase 2 pilot trial to optimise pharmacometric evaluations in Chagas disease (CHARM: CHAgas disease PharMacometrics)

Chagas disease is a neglected disease caused by Trypanosoma cruzi that currently affects about 7 million people in the Americas and the American diaspora. Only two drugs are available to treat Chagas disease, both are associated with a high incidence of adverse events, particularly in adults, and they are also complex to administer. New treatments are needed urgently, but there is no established method of evaluating new drugs. We describe the study protocol for a pilot phase 2 descriptive observational study of parasite dynamics within the host, followed by a randomised evaluation of the pharmacokinetic-pharmacodynamic properties of subcurative doses of anti-chagasic drugs in patients with chronic Chagas disease. This study is divided into three stages. The general objective of the study is to characterise the dynamics of the parasite within the host at steady state and the pharmacokinetic-pharmacodynamic relationships for each of the three drugs studied. This is based on characterising the structure and parameters of a pharmacodynamic model of parasite turnover within the host. Each stage of the study targets specific key parameters in the pharmacodynamic model of parasite dynamics (both the blood stage and the tissue stage) for individual research participants. The primary outcome measure for all three stages is blood-stage parasite density, measured by quantitative PCR. Upon completion, research participants will receive definitive treatment for Chagas disease in accordance with national guidelines. Registration ISRCTN (ISRCTN26467068; 01/07/2021).

New Antagonists of the Membrane Androgen Receptor OXER1 from the ZINC Natural Product Database.

OXER1 (oxoeicosanoid receptor 1) was deorphanized in 1993 and found to be the specific receptor for the arachidonic acid metabolite 5-oxo-ETE. Recently, we have reported that androgen binds to this receptor also, being a membrane androgen receptor, triggering a number of its membrane-mediated actions (cell migration, apoptosis, cell proliferation, Ca2+ movements). In addition, our previous work suggested that a number of natural monomeric and oligomeric polyphenols interact with OXER1, acting similar to testosterone. Here, we interrogated the natural product chemical space and identified nine polyphenolic molecules with interesting in silico pharmacological activities as putative OXER1 antagonists. The molecule with the best pharmacokinetic–pharmacodynamic properties (ZINC15959779) was purchased and tested on OXER1, in prostate cancer cell cultures. It showed that it has actions similar to those of testosterone in inhibiting cAMP, while it had no action in intracellular Ca2+ mobilization or actin cytoskeleton rearrangement/migration. These results are discussed under the prism of structure–activity relationships and in silico models of the OXER1 binding groove. We suggest that these compounds, together with the previously reported (poly)phenolic compounds, can be lead structures for the exploration of the anti-inflammatory and antiproliferative effects of OXER1 antagonists.

Gastroparesis, metoclopramide, and tardive dyskinesia: Risk revisited.

Metoclopramide is primarily a dopamine receptor antagonist, with 5HT3 receptor antagonist and 5HT4 receptor agonist activity, and used as an antiemetic and gastroprokinetic since almost 50years. Regulatory authorities issued restrictions and recommendations regarding long-term use of the drug at oral doses exceeding 10mg 3-4 times daily because of the risk for development of tardive dyskinesia. The aim of our study was to review mechanism(s) of action and pharmacokinetic-pharmacodynamic properties of metoclopramide, as well as the risk of metoclopramide-induced tardive dyskinesia, factors that may change drug exposure in humans, and to summarize the clinical context for appropriate use of the drug. A PubMed, Google Scholar, and Cross Reference search was done using the key words and combined searches: drug-drug interaction, gastroparesis, metoclopramide, natural history, pharmacokinetics, pharmacodynamics, drug-drug interaction, outcome, risk factors, tardive dyskinesia. Data show that the risk of tardive dyskinesia from metoclopramide is low, in the range of 0.1% per 1000 patient years. This is far below a previously estimated 1%-10% risk suggested in treatment guidelines by regulatory authorities. High-risk groups are elderly females, diabetics, patients with liver or kidney failure, and patients with concomitant antipsychotic drug therapy, which reduces the threshold for neurological complications. The risk of tardive dyskinesia due to metoclopramide is far below approximated numbers in treatment guidelines. This risk and the influence of known risk factors should be considered when starting a course of metoclopramide for treatment of gastroparesis.

Population pharmacokinetic and pharmacodynamic properties of artesunate in patients with artemisinin sensitive and resistant infections in Southern Myanmar

BackgroundArtemisinins are the most effective anti-malarial drugs for uncomplicated and severe Plasmodium falciparum malaria. However, widespread artemisinin resistance in the Greater Mekong Region of Southeast Asia is threatening the possibility to control and eliminate malaria. This work aimed to evaluate the pharmacokinetic and pharmacodynamic properties of artesunate and its active metabolite, dihydroartemisinin, in patients with sensitive and resistant falciparum infections in Southern Myanmar. In addition, a simple nomogram previously developed to identify artemisinin resistant malaria infections was evaluated.MethodsFifty-three (n = 53) patients were recruited and received daily oral artesunate monotherapy (4 mg/kg) for 7 days. Frequent artesunate and dihydroartemisinin plasma concentration measurements and parasite microscopy counts were obtained and evaluated using nonlinear mixed-effects modelling.ResultsThe absorption of artesunate was best characterized by a transit-compartment (n = 3) model, followed by one-compartment disposition models for artesunate and dihydroartemisinin. The drug-dependent parasite killing effect of dihydroartemisinin was described using an Emax function, with a mixture model discriminating between artemisinin sensitive and resistant parasites. Overall, 56% of the studied population was predicted to have resistant malaria infections. Application of the proposed nomogram to identify artemisinin-resistant malaria infections demonstrated an overall sensitivity of 90% compared to 55% with the traditional day-3 positivity test.ConclusionThe pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to differentiate between drug sensitive and resistant infections in these patients. More than half of all patients recruited in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights its potential clinical usefulness.

Optimal individualized dosing strategies: A pharmacologic approach to developing dynamic treatment regimens for continuous-valued treatments.

There have been considerable advances in the methodology for estimating dynamic treatment regimens, and for the design of sequential trials that can be used to collect unconfounded data to inform such regimens. However, relatively little attention has been paid to how such methodology could be used to advance understanding of optimal treatment strategies in a continuous dose setting, even though it is often the case that considerable patient heterogeneity in drug response along with a narrow therapeutic window may necessitate the tailoring of dosing over time. Such is the case with warfarin, a common oral anticoagulant. We propose novel, realistic simulation models based on pharmacokinetic-pharmacodynamic properties of the drug that can be used to evaluate potentially optimal dosing strategies. Our results suggest that this methodology can lead to a dosing strategy that performs well both within and across populations with different pharmacokinetic characteristics, and may assist in the design of randomized trials by narrowing the list of potential dosing strategies to those which are most promising.

Pharmacokinetics and pharmacodynamics of the short-acting sedative CNS 7056 in sheep

BackgroundCNS 7056 is a new short-acting esterase-metabolized benzodiazepine. We report the first pharmacokinetic (PK) and pharmacodynamic (PD) study of CNS 7056 and its inactive metabolite CNS 7054 in sheep. MethodsThe stability of CNS 7056 in blood samples was examined ex vivo. Six sheep were prepared with physiological instrumentation, and were given doses of 0.37, 0.74, and 1.47 mg kg−1 (2 min infusion) of CNS 7056 in alternating order on separate days. ResultsCNS 7056 was degraded in warm whole sheep blood (23% over 2 h), but not in plasma or blood stored on ice. Using non-compartmental analysis (NCA), CNS 7056 had a mean (sd) clearance of 4.52 (0.96) litre min−1 and a terminal half-life of 21.3 (10.9) min. There was a rapid conversion of CNS 7056 to its metabolite CNS 7054, which had a terminal half-life of 22.5 (3.4) min. The arterial kinetics of CNS 7056 could be described by a three-compartment model, with volumes of 1.9, 3.9, and 79 litre, a clearance of 4.2 litre min−1, and inter-compartmental clearances of 2.85 and 1.44 litre min−1, while the metabolite could be described by a two-compartment model. Cardiac output was an important covariate. Sedation as measured by the alpha power band of the EEG showed rapid onset and offset. The t1/2,ke0 for sedation was 1.78 min, and the EC50 was 0.10 µg ml−1. ConclusionsCNS 7056 has PK–PD properties compatible with its potential human use as a short-acting i.v. sedative.

Utilisation des carbapénèmes en pédiatrie

Increasing frequency of infections due to multi-drug resistant organisms is currently observed in the adult and pediatric population. Therapeutic options are unfortunately limited to treat such infections. It is the clinician's responsibility to use wide-spectrum antibiotics when appropriate, but also to limit the use of these drugs to the sole situations where such a potent treatment is required. Carbapenems are the most efficient beta-lactams, especially against gram-negative bacilli, and the most preserved from resistance so far. This review summarizes microbiological, pharmacokinetic and pharmacodynamic characteristics of currently available cabapenems. Their clinical use in different pediatric settings is then discussed, based on available published evidence. In order to maintain their microbiological efficiency and to limit the emergence of carbapem-resistant strains, carbapenems should be exclusively used for infections due to gram-negative bacilli showing resistance to other beta-lactams. In the next years meropenem should logically replace imipenem indications regarding its superior pharmacokinetic-pharmacodynamic properties, its higher tolerance and its easier use in the pediatric population.

Antibiotic Treatment of Animals Infected withBorrelia burgdorferi

Despite resolution of the objective manifestations of Lyme disease after antibiotic treatment, a minority of patients have fatigue, musculoskeletal pain, and/or difficulties with concentration or short-term memory of uncertain etiology; these are called post-Lyme disease symptoms or, in more severe cases, post-Lyme disease syndrome or "chronic Lyme disease." Several recent studies in which Borrelia burgdorferi-infected animals were treated with antibiotic therapy have demonstrated the presence of PCR positivity for B. burgdorferi DNA in the absence of culture positivity. In mice that were treated with antibiotic therapy, residual spirochetes could be taken up by ticks during a blood meal and could be transmitted to SCID mice. These spirochetes are attenuated; their presence is not associated with either inflammation or disease. In this review the methodology and findings of these studies are critically analyzed, and the significance of the results with regard to human Lyme disease is evaluated, with special emphasis on whether these studies provide useful insights into post-Lyme disease syndrome. A serious methodological concern is the failure to consider the pharmacokinetic-pharmacodynamic properties of the antibiotic in choosing the dosage regimen used. We conclude that there is no scientific evidence to support the hypothesis that such spirochetes, should they exist in humans, are the cause of post-Lyme disease syndrome.

New Antimicrobial Molecules and New Antibiotic Strategies

Drug options for treatment of infections are increasingly limited. The pharmaceutical industry has found it difficult to discover new antimicrobial agents, and only two novel classes of antibiotics, the oxazolidinones and the cyclic lipopeptides, have entered the market since the late 1960s. Few new agents have reached the market in the last decade with potential interest for community-acquired pneumonia (CAP) treatment, including linezolid (the first oxazolidinone in clinical use), new fluoroquinolones, cefditoren, ertapenem, and telithromycin. Agents currently in clinical development include other novel quinolones and ketolides, broad-spectrum cephalosporin derivatives, faropenem, several glycopeptides, and iclaprim. Other molecules are considered to be promising candidates for the future. In addition to the foregoing agents, alternative treatment approaches have also been introduced into clinical practice, which include the administration of the appropriate antimicrobials in a timely manner and the consideration of the pharmacokinetic-pharmacodynamic properties of the agent(s).

Increased sensitivity to diltiazem hypotensive effect in an experimental model of high-renin hypertension

Abstract Objectives The aim of this work was to evaluate the pharmacokinetic–pharmacodynamic properties of diltiazem in an experimental model of high-renin hypertension, such as the aortic coarctated (ACo) rat, to further characterize the responsiveness of this model to calcium channel blockers. Methods A ‘shunt’ microdialysis probe was inserted in a carotid artery of anaesthetized ACo and control sham-operated (SO) rats for simultaneous determination of diltiazem plasma concentrations and their effects on mean arterial pressure and heart rate after the intravenous application of 3 and 6 mg/kg of the drug. Correlation between plasma levels and cardiovascular effects was established by fitting the data to a modified Emax model. Key findings Volume of distribution was greater in ACo than in SO rats. Diltiazem plasma clearance (Cl) was significantly greater in ACo rats than in normotensive SO rats after administration of diltiazem (6 mg/kg). Moreover, Cl increased with dose in ACo but not in SO rats. No differences were observed in the maximal bradycardic effect comparing both experimental groups, and sensitivity (S0) to diltiazem chronotropic effect was similar comparing SO and ACo rats. Differences were not found in the maximal response of the hypotensive effect comparing SO and ACo rats, but the S0 to diltiazem hypotensive effect was greater in ACo rats than in SO rats. Conclusions ACo induced profound changes in diltiazem pharmacokinetic behaviour. In addition, our results suggested an increased sensitivity to diltiazem blood pressure lowering effect in experimental renovascular hypertension with high-renin levels.

Cardiotoxicity of Oral Methadone as an Analgesic–-Recommendations for Safe Use

Once used only as third-line therapy in the management of chronic pain states, methadone is now being used as first- and second-line therapy. Most risks and the stigma associated with methadone use have been known for years. Only over the past decade or so have the unique pharmacokinetic-pharmacodynamic properties and methods for conversion from other opioids to methadone been established. Pertinent English-language literature was obtained from MEDLINE/PUBMED and EMBASE searches (1966-June 2009). This paper provides an overview of the cardiotoxicity of oral methadone, with an emphasis on its use as an analgesic. Cardiotoxicity during its use in the maintenance of opioid addiction has also been reviewed due to the wealth of epidemiologic, risk factor, and correlative analytic data contained therein. A series of recommendations are provided to improve the cardiac safety profile of oral methadone used for analgesia. In addition, there is a discussion of settings and patient types which may impact upon these recommendations.

Increased sensitivity to diltiazem hypotensive effect in an experimental model of high-renin hypertension

The aim of this work was to evaluate the pharmacokinetic-pharmacodynamic properties of diltiazem in an experimental model of high-renin hypertension, such as the aortic coarctated (ACo) rat, to further characterize the responsiveness of this model to calcium channel blockers. A 'shunt' microdialysis probe was inserted in a carotid artery of anaesthetized ACo and control sham-operated (SO) rats for simultaneous determination of diltiazem plasma concentrations and their effects on mean arterial pressure and heart rate after the intravenous application of 3 and 6 mg/kg of the drug. Correlation between plasma levels and cardiovascular effects was established by fitting the data to a modified Emax model. Volume of distribution was greater in ACo than in SO rats. Diltiazem plasma clearance (Cl) was significantly greater in ACo rats than in normotensive SO rats after administration of diltiazem (6 mg/kg). Moreover, Cl increased with dose in ACo but not in SO rats. No differences were observed in the maximal bradycardic effect comparing both experimental groups, and sensitivity (S0) to diltiazem chronotropic effect was similar comparing SO and ACo rats. Differences were not found in the maximal response of the hypotensive effect comparing SO and ACo rats, but the S0 to diltiazem hypotensive effect was greater in ACo rats than in SO rats. ACo induced profound changes in diltiazem pharmacokinetic behaviour. In addition, our results suggested an increased sensitivity to diltiazem blood pressure lowering effect in experimental renovascular hypertension with high-renin levels.

Recombinant interferon-alpha2b poly(lactic-co-glycolic acid) microspheres: pharmacokinetics-pharmacodynamics study in rhesus monkeys following intramuscular administration

Investigation into pharmacokinetic-pharmacodynamic properties of interferon- alpha (IFN-alpha)2b-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres (MS) in rhesus monkey primates. IFN-alpha2b was loaded with biodegradable PLGA with 3 inherent viscosities using a double emulsion and solvent evaporation method. The particle size, surface morphology, and in vitro release profiles were investigated. Two groups of rhesus monkeys (n=3) were injected intramuscularly with either 3 MIU/kg commercial IFN-alpha2b lyophilized powder or IFN-alpha2b-loaded PLGA microspheres (inherent viscosity of 0.89 dL/g). In vitro release was determined by Lowry protein assay. The serum IFN and neopterin levels were determined by the enzyme-linked immunosorbent assay (ELISA) method to evaluate biological activity of the microspheres in rhesus monkeys. The IFN-alpha2b microspheres with 3 inherent viscosities (0.39, 0.89, and 1.13 dL/g) were entirely spherical and had a smooth surface. The average diameter of each type was 45.55, 81.23, and 110.25 microm, respectively. The in vitro release was 30 d. The pharmacokinetic-pharmacodynamic properties between the IFN-alpha2b microspheres and IFN-alpha2b lyophilized powder were significantly different (P<0.05). The drug residence time for the IFN-alpha2b of the PLGA microsphere with an inherent viscosity of 0.89 dL/g in plasma significantly increased and had a longer time of biological effects in rhesus monkeys following intramuscular administration.

The First Years of Linezolid Experience in Clinical Practice: A Balance and Future Implications

Multi-antibiotic resistant Gram-positive cocci, which include Staphylococcus aureus, the coagulase-negative staphylococcal group, Enterococcus faecalis and Enterococcus faecium, and other streptococci, represent emerging pathogens especially in the setting of the immunocompromised, hospitalized patients, in particular when surgery, invasive procedures, or prosthetic implants are of concern, patients are admitted in intensive care units, or underlying chronic disorders and immunodeficiency are to be considered, and broad-spectrum antibiotics or immunosuppressive drugs are needed for prolonged administration. During the recent years, the phenomenon of multi-resistant Gram-positive cocci is spreading from the Hospital into the community, where the retrieval of such microorganism is progressively increasing. The spectrum of available antimicrobial compounds for an effective management of these relevant infections is significantly impaired in selection and clinical efficacy by the emerging and spread of methicillin-resistant and more recently glycopeptide-resistant Gram-positive microbial strains. The first oxazolidinone derivative linezolid, together with the recently licensed quinupristin-dalfopristin, daptomycin and tigecycline, followed by a number of glycopeptides, fluoroquinolones, and other experimental compounds on the pipeline or approaching the market in the year 2006, represent an effective response to the great majority of these concerns. Because of their innovative mechanisms of action, their maintained or enhanced activity against multiresistant pathogens, their effective pharmacokinetic-pharmacodynamic properties, their frequent possibility of synergistic activity with other compounds effective against Gram-positive pathogens, and a diffuse potential for a safe and easy administration, also when compromised patients are of concern. The main problems related to the epidemiological and clinical features of multiresistant Gram-positive infection, the potential clinical indications of all recently available compounds compared with the standard of care of treatment of resistant Gram-positive infections, and updated data on efficacy and tolerability of linezolid as the golden standard compound for vancomycinresistant Gram-positive cocci in multiple clinical situations, are outlined and updated on the ground of an extensive review of all the available. Recent evidences are commented from the international literature. Keywords: Linezolid, oxazolidinones, resistant gram-positive organisms, staphylococci, enterococci

Pharmacokinetic and Pharmacodynamic Interaction Between Irbesartan and Hydrochlorothiazide in Renal Hypertensive Dogs

Combined irbesartan/hydrochlorothiazide (HCTZ) formulations are often used clinically. Pharmacokinetic-pharmacodynamic (PK/PD) modeling was applied to investigate the pharmacokinetic and pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs at non-steady-state and steady-state. The renal hypertensive dogs were treated with oral irbesartan alone, or HCTZ alone, or the combination of irbesartan and HCTZ for 8 days. Blood pressure and plasma concentrations were measured and pharmacokinetic-pharmacodynamic parameters were analyzed. Irbesartan showed a two-compartment model pharmacokinetic profile. The concentration-time course of irbesartan was not changed by HCTZ, but irbesartan increased the peak plasma concentration and area under the curve of HCTZ at steady-state. HCTZ had no blood pressure lowering effect at non-steady-state. Irbesartan plus HCTZ had greater blood pressure lowering action than irbesartan alone. HCTZ increased actions of irbesartan. Hysteresis loops were found between effect and plasma concentrations of irbesartan after a single dose. However, hysteresis loops disappeared at steady state with more rapid realization of maximum concentration and effects. The relationship between effects and effect-compartment concentrations of the drugs was represented by a sigmoid Emax model. The results suggest synergistic pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs and some differences of pharmacokinetic-pharmacodynamic properties between irbesartan and irbesartan/HCTZ combinations at non-steady-state and steady state.

Pharmacokinetics and clinical effectiveness of methylphenidate.

Methylphenidate is prescribed for over 90% of children in the US diagnosed as having attention-deficit hyperactivity disorder (ADHD). Although ADHD has been widely studied, the use of methylphenidate in ADHD still poses a number of unresolved questions, including its pharmacodynamic characteristics (drug concentration-effect relationship) and the effect of long term treatment on the patient's psychopathology later in life. The objective of this review is to provide an analysis of the pharmacokinetic-pharmacodynamic properties and therapeutic effectiveness of methylphenidate that may help to answer some of these questions. Methylphenidate has 2 chiral centres, but the drug used in therapy comprises only the threo pair of enantiomers. d-threo-Methylphenidate is more potent than the l-enantiomer. Methylphenidate is administered as a racemic mixture that undergoes stereoselective clearance. Methylphenidate is a short-acting stimulant with a duration of action of 1 to 4 hours and a pharmacokinetic half-life of 2 to 3 hours. Maximum drug concentration after oral administration occurs at about 2 hours. Methylphenidate is absorbed well from the gastrointestinal tract and easily passes to the brain. Methylphenidate is efficacious for short term treatment for children with ADHD. Its mechanism of action is not understood, but may be associated with its influence on multiple neurotransmitters, especially the release and reuptake of dopamine in the striatum. There is marked individual variability in the dose-response relationship for methylphenidate, and therefore dosage must be titrated for optimal effect and avoidance of toxicity in each child. It is unclear whether this variability is predominantly pharmacokinetic or pharmacodynamic. If variable stereoselective metabolism occurs clinically, therapeutic drug monitoring of methylphenidate will require the application of chiral assay methods for the analysis of the active component, d-threo-methylphenidate. It is difficult to predict which children will have a favourable response to methylphenidate. Nonetheless, several studies have been published linking the severity of ADHD in children with improved clinical response to methylphenidate. The use of individual single-blind medication trials may be a practical solution to this problem. Additionally, the targeted condition warrants careful consideration, since different conditions (e.g. misbehaviour or poor academic performance) may require different regimens. Further studies of the relationship between the pharmacokinetic and pharmacodynamic properties of methylphenidate are required to allow the development of optimal dosage regimens.

Clinical pharmacokinetics of sedatives in neonates.

Sedation is currently administered to neonates experiencing pain and stress during intensive care for medical diseases, as well as postoperatively. Drugs commonly used for sedation in neonates include benzodiazepines (midazolam and lorazepam), chloral hydrate and opioids (fentanyl and morphine). Sedation protocols and dosage schedules are, in most cases, adapted from those which have been developed in children and even adults. The effectiveness and safety of the sedative agents remain underevaluated, however, due to the difficulties of quantifying pain and stress in neonates, and because of the limited use of validated scoring methods by practitioners. Among the benzodiazepines, midazolam is probably the drug of choice for continuous sedation. However, its elimination is delayed in the neonatal period and hypotension may occur when given as a bolus injection or when taken with opioids. Lorazepam requires further evaluation to exclude severe neurotoxicity. Chloral hydrate is administered orally, but because of its delayed elimination and risk of accumulation, a single administration for short term sedation is recommended. Among opioids, fentanyl (which was initially administered for postoperative analgesia) is now prescribed for sedation during mechanical ventilation. Tolerance and dependence may develop rapidly, limiting its usefulness for prolonged sedation. Although extensively studied in neonates, the efficacy and safety of morphine are not clearly determined, because of the limited number of patients included in individual studies. In addition, important interindividual differences in metabolism render dosage recommendations difficult. Alfentanil and sufentanil need further investigations to define their pharmacokinetic-pharmacodynamic properties in neonates. Although the choice of drug is important, the way the drug is used and monitored is equally important. All the drugs used for the sedation of neonates have large inter- and intraindividual differences in disposition, justifying specific pharmacological knowledge and individual dosage adjustments based on clinical evaluation of the patient and the monitoring of drug concentrations.