Search Menu Abstract Objectives: To analyse the pharmacokinetic basis for the use of extended-interval dosage regimens of gentamicin in neonates using population pharmacokinetics. A one-compartment pharmacokinetic model and non-linear mixed-effects modelling were used to assess the population pharmacokinetic model. Results: Weight W and postnatal age PA were the covariates that influenced the pharmacokinetic parameters of gentamicin. The predictive performance of the model in the population validation was adequate for clinical purposes. The optimized population model allowed us to simulate gentamicin serum levels and their variability, in this kind of patient, when extended-interval dosage administration regimens were implemented. Different factors and developmental variables may alter the dosage requirements of gentamicin, such as birthweight, gestational age GA , post-natal age PA and renal function, among others.
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Sonu Bhaskar: se. This article has been cited by other articles in PMC. Abstract Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs.
In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles NP are first reviewed.
Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion.
Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as fluorescent protein tomography and multispectral optoacoustic tomography.
Overall, great potential is foreseen for nanocarriers in medical diagnostics, therapeutics and molecular targeting. A proposed roadmap for ongoing and future research directions is therefore discussed in detail with emphasis on the development of novel approaches for functionalization, targeting and imaging of nano-based drug delivery systems, a cutting-edge technology poised to change the ways medicine is administered.
Introduction Nanotechnology has brought a new generation of lightweight materials with superior mechanical and electrical properties.
Engineered nanoparticles NPs are normally embedded in the matrix of other composites to enhance certain characteristics.
Biology and medicine, however, usually employ dispersed NPs, for instance as fluorescent biological labels [ 1 - 3 ], drug and gene delivery agents [ 4 , 5 ], bio-detection of pathogens [ 6 ], detection of proteins [ 7 ], probing of DNA structure [ 8 ], tissue engineering [ 9 , 10 ], tumour destruction via heating hyperthermia [ 11 ], separation and purification of biological molecules and cells [ 12 ], magnetic resonance imaging MRI contrast enhancement [ 13 ] and phagokinetic studies [ 14 ].
The ability of the engineered nanoparticles to interact with cells and tissues at a molecular level provides them with a distinct advantage over other polymeric or macromolecular substances. While the advent of nanotechnology made its first mark on consumer products, until recently, very little was known about their potential medical applications.
NPs have long been noticed to pass across the BBB [ 15 ], a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from passing through. This in itself provides a substantial advantage for drug delivery systems across the BBB, which can pave the way for effective treatments of many central nervous system disorders.
This feature, however, was not fully exploited till two decades later. As such, keeping in mind the paucity of therapies for such debilitating disorders, advances in the targeting of drugs to the central nervous system CNS will be the main stay for the future success and development of nanotechnology-based diagnostics application of NPs in therapy and diagnostics in neurology.
To this end, efficient delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain is hindered by the BBB, the blood cerebrospinal fluid barrier BCSF , or other specialized CNS barriers [ 16 ]. The average molecular mass of the CNS active drug was Daltons. Modern ageing societies require therefore a broader spectrum of treatments for neurological disorders.
Functionalization of NPs is indeed the first and perhaps foremost step towards nano-scale drug delivery systems. NPs should inherit a number of desirable characteristics from their functionalization.
Drug-carrying capabilities are as important as transport, organ targeting and eventual excretion. Affinity of functional groups to tissue specific transport methods is clearly a challenging problem. It is known that some transport molecules such as growth factors, insulin and transferrin can potentially increase the efficiency and kinetics of drugs across a range of tissues.
Once nanomaterials are enhanced with drug-carrying and transport capabilities, in vivo imaging markers, such as fluorescent dyes for optical imaging, is the next landmark to achieve.
No review on functionalization of nanocarriers is complete without mentioning imaging technologies capable of their effective visualization. Beyond improvements in overall image quality and spatial resolution, imaging modalities have been entrusted with the challenge of capturing dynamic processes involving various biological system components as well as their respective interactions. For example, the ability to resolve and monitor transmigration ability of various types of biomolecules across the BBB in vivo is a daunting challenge.
In this context, we give a special attention to the most recent developments in the field of fluorescence-based imaging techniques that have become an integral part of modern biological discovery process, especially in the pre-clinical small-animal-based research. Initially, fluorescence imaging was limited to ex vivo and in vitro applications with an exception of several intravital microscopy and photographic imaging approaches [ 21 - 23 ]. Although helpful in some cases, these methods fall short to the potential of more recent trans-illumination and tomographic techniques that allow non-invasive fluorescence images in vivo [ 24 ].
Powerful capabilities are found when those techniques are co-registered with precise in vivo anatomical views of the brain provided by MRI or X-ray computed tomography CT. An additional enormous potential lie ahead with the recent advances of high resolution optoacoustic molecular imaging approaches, such as multispectral optoacoustic tomography MSOT [ 25 ].
All these are expected to facilitate the development of novel imaging-based diagnostic and therapeutic nanoprobes for early diagnosis and therapy of various disorders of the brain following systematic administration. In this review, we highlight some of the ongoing trends in molecular tomographic imaging of live animals and present insights into exploiting targeting of brain tumours for therapeutic and diagnostics purpose.
Next section will discuss the physiology of BBB, which plays an important role in designing novel platforms to enable access to the brain. Blood Brain Barrier: A gateway to neurological diseases Treatment of neurological diseases such as brain tumours, inborn metabolic errors e.
The advancement of pharmacological drug delivery to the brain has been constrained due the existence of protective barriers which restricts the passage of foreign particles into the brain. Therefore, the efficient design of non-invasive nanocarrier systems that can facilitate controlled and targeted drug delivery to the specific regions of the brain is a major challenge in drug development and delivery for the neurological diseases [ 28 , 29 ].
It becomes crucial to understand the structural composition as well as the functions of the factors that regulate permeability of the substances across the BBB. For that reason, we will briefly discuss the main transporters that mediate the transport of substances across the brain.
We can see how BBB acts as a neuroprotective shield by protecting the brain from most substances in the blood, supplying brain tissues with nutrients, and filtering harmful compounds from the brain back to the bloodstream [ 30 ].
BBB is constituted by the brain endothelial cells which form the anatomical substrate called cerebral microvascular endothelium. It regulates the transport of solutes and other substances including drugs in and out of the brain, leukocyte migration, and maintains the homeostasis of the brain microenvironment, which is crucial for neuronal activity and proper functioning of CNS.
The cerebral microvascular endothelium, together with astrocytes, pericytes, neurons, and the extracellular matrix, constitute a "neurovascular unit" that is essential for the health and function of the CNS [ 31 ]. The transport of solutes and other substances across BBB is strictly constrained through both physical tight junctions TJs and adherents junctions AJs and metabolic barriers enzymes, diverse transport systems and hence excluding very small, electrically neutral and lipid soluble molecules.
Thus, conventional pharmacological drugs or chemotherapeutic agents are unable to pass through the barrier.
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Recently, detailed pharmacokinetic studies in pregnant sheep have demonstrated that DPHM readily crosses the ovine placenta, and is eliminated from the fetus by placental and non-placental pathways. The purpose of this study is to investigate the components of the fetal non-placental elimination i. Since stable isotope techniques were to be employed, synthesis of stable isotope labeled DPHM i. Overall, the total non-placental clearance of DPHM measured by direct methods i.
CROSS-REFERENCE TO RELATED APPLICATIONS
The compound of claim 7, wherein A the compound is according to Formula 18 like Type J and one or more of the following features are satisfied: R54 is selected from the group consisting of: 4,6-dimethylpyrimidine; 2,6-dimethoxypyrimidine; 6-methoxypyrimidine; 5-ethyl 1,3,4-Thiadiazole ; 5-methylIsoxazole; 3-methoxypyridazinamine, 2-thiazole; and 2-methoxypyrazine. R55 is selected from the group consisting of hydrogen and methyl; the compound is selected from the group consisting of: B the compound according to Formula 19 like Type K is C the compound according to Formula 20 like Type L is selected from the group consisting of: D the compound according to Formula 21 like Type M is E the compound of Formula 22 like Type N is selected from the group consisting of: or F the compound of Formula 23 like Type O is selected from the group consisting of: 9. The compound of claim 10, wherein A the compound is according to Formula 32 like Type H and one or more of the following features are satisfied: R and R are independently selected from the group consisting of hydrogen; trifluoromethyl; methoxy; and chloro; R or R is hydrogen; R and R are independently selected from the group consisting of halogen and trifluoromethyl; R selected from the group consisting of halogen and straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; R and R are independently selected from the group consisting of hydrogen, methyl, and methoxy; R and R are independently selected from the group consisting of hydrogen and chloro; R is selected from the group consisting of hydrogen; chloro; methoxy; and methyl. R of Formula 32 is selected from the group consisting of hydrogen; methyl; and ethyl; or the compound is selected from the group consisting of: or B the compound is according to Formula 33 like Type I and one or more of the following features are satisfied: R and R are independently selected from the group consisting of: hydrogen; methyl; and chloro. R and R are independently selected from the group consisting of: hydrogen; trifluoromethyl; and chloro. R is chloro.