Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery

Alavijeh, Mohammad S.; Chishty, Mansoor; Qaiser, M. Zeeshan; Palmer, Alan M.

doi:10.1602/neurorx.2.4.554

Cited by 411 publications

(272 citation statements)

References 85 publications

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“…26 AD is the most common form of dementia, and the greatest risk factor for AD is age. It is estimated that 10% of people over the age of 65 are affected by AD 4 and by 2050, the number of people with AD in the US will increase threefold. 45 The definite diagnosis of AD is made upon histological verification, established by biopsy or at autopsy, of two main hallmarks: extracellular amyloid plaques and intracellular neurofibrillary tangles, which enclose hyperphosphorylated tau protein.…”

Section: Alzheimer Diseasementioning

confidence: 99%

“…Estimates state that 1% of people over age 60 are affected by PD, the leading cause of the movement disorder called Parkinsonism. 4 Clinical features of PD include tremor at rest, bradykinesia, rigidity and flexed posture. 48 Pathologically, the key deficit in PD has been considered to be the loss of dopaminergic neurons in the substantia nigra, which causes consequent reduction of dopamine level.…”

Section: Parkinson Diseasementioning

confidence: 99%

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Nanoparticle transport across the blood brain barrier

et al. 2016

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While the role of the blood-brain barrier (BBB) is increasingly recognized in the (development of treatments targeting neurodegenerative disorders, to date, few strategies exist that enable drug delivery of non-BBB crossing molecules directly to their site of action, the brain. However, the recent advent of Nanomedicines may provide a potent tool to implement CNS targeted delivery of active compounds. Approaches for BBB crossing are deeply investigated in relation to the pathology: among the main important diseases of the CNS, this review focuses on the application of nanomedicines to neurodegenerative disorders (Alzheimer, Parkinson and Huntington's Disease) and to other brain pathologies as epilepsy, infectious diseases, multiple sclerosis, lysosomal storage disorders, strokes.

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Section: Alzheimer Diseasementioning

confidence: 99%

Section: Parkinson Diseasementioning

confidence: 99%

Nanoparticle transport across the blood brain barrier

et al. 2016

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“…44 On the other hand, neutral compounds with a polar surface area (PSA) lower that 60 Å 2 and molecular mass below 450 Da have better permeation possibility. [45][46][47] Another enzyme similar to AChE is butyrylcholinesterase (BChE), which displays about 65% of amino acid sequence similarity with AChE. 48 However, while AChE is involved in the control of nerve pulse transition by hydrolysis of acetylcholine in cholinergic synapses, BChE performs actions in pharmacological and toxicological processes by hydrolysis of drugs containing ester groups and some AChE inhibitors.…”

Section: Introductionmentioning

confidence: 99%

The effect of neutral oximes on the reactivation of human acetylcholinesterase inhibited with paraoxon

Ribeiro¹,

Prates²,

Alves³

et al. 2012

J. Braz. Chem. Soc.

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Importantes agentes para defesa contra armas de guerra química são reativadores da acetilcolinesterase humana (huAChE) inibida por compostos organofosforados neurotóxicos (OP), e precisam de uma permeabilidade razoável pela barreira hematoencefálica (HB). Neste trabalho, oximas neutras, que penetram HB melhor do que as oximas catiônicas atualmente utilizadas como agentes de defesa, foram testadas como reativadores da huAChE inibida com paraoxon usando o método de Ellman modificado e pralidoxima (2-PAM) como padrão positivo. A oxima neutra mais ativa foi a 2-tiofenoaldoxima, que reativou 93% da huAChE inibida, sendo 12% mais eficiente do que a 2-PAM. Os resultados mostraram que oximas neutras simples possuem potencial para atuarem como antídotos para intoxicação com OPs neurotóxicos, sugerindo maior investigação no desenvolvimento de agentes de defesa neutros.Important defense agents against chemical warfare weapons, which are reactivators of human acetylcholinesterase (huAChE) inhibited by neurotoxic organophosphorus compounds (OP), need a reasonable permeation of the hematoencephalic barrier (HB). In this work, neutral oximes, which permeate HB better than the cationic oximes currently used as defense agents, were tested as reactivators of huAChE inhibited with paraoxon using the modified Ellman test with pralidoxime (2-PAM) as positive standard. The most active neutral oxime was (thiophen-2-yl)aldoxime, which reactivated 93% of the inhibited huAChE and was 12% more effective than 2-PAM. The results showed that simple neutral oximes have potential to function as antidotes for intoxication with neurotoxic OPs, suggesting further research on the development of neutral defense agents.Keywords: neutral oximes, huAChE reactivation, paraoxon, chemical warfare, (thiophen-2-yl)aldoxime IntroductionIntoxication with neurotoxic organophosphorus compounds is a serious problem caused by some pesticides used in agriculture, such as paraoxon (1) and malathion (2) ( Figure 1) and chemical warfare agents. [1][2][3][4][5][6][7][8][9][10][11] According to the World Health Organization, there are about 220,000 intoxications with organophosphorus pesticides throughout the world every year, leading to approximately 20,000 deaths. 1,[12][13][14] The most dangerous neurotoxic compounds are the chemical warfare agents soman (3), sarin (4), tabun (5) and VX (6) ( Figure 1). Though their use is prohibited by the United Nations, these agents have been employed as weapons by terrorist groups and by countries that did not sign the Chemical Weapon Convention administered by the Organization for the Prohibition of Chemical Weapons (OPCW).The principal target for the action of neurotoxic organophosphorus compounds is the enzyme acetylcholinesterase (AChE), a serine hydrolase that controls the nerve impulses at the cholinergic receptors in the central and peripheral nervous systems. 1,15-20 As shown in Ribeiro et al. 1217 Vol. 23, No. 7, 2012 Figure 2, the function of AChE (7) is the hydrolysis of the nerve impulse transmitter acetylcholine...

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“…In order to improve the understanding of drug efficacy and safety characteristics, it is desirable to investigate the drug metabolism in animals or humans [3,4]. These metabolism studies involve metabolic stability, cytochrome P-450 (CYP-450) induction or inhibition and metabolite identification.…”

Section: Editorialmentioning

confidence: 99%

Editorial: Drug Metabolism and Toxicology

Bandu¹,

Kim²

2016

J Drug Metab Toxicol

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EditorialA drug metabolism study is an important aspect of the early drug discovery and development process [1,2]. In order to improve the understanding of drug efficacy and safety characteristics, it is desirable to investigate the drug metabolism in animals or humans [3,4]. These metabolism studies involve metabolic stability, cytochrome P-450 (CYP-450) induction or inhibition and metabolite identification. As drugs are xenobiotics to living organisms, CYP-450 biotransform them to less toxic, less active and more hydrophilic forms in order to enhance their excretion in urine [5,6]. However, metabolism can lead to formation of active metabolites, reactive or other toxic metabolites. Identification of reactive or toxic metabolites is essential in the drug discovery and development process to optimize lead compounds for further development and to avoid the toxicity, and helps to modify the structure by means of chemical transformations [4,7,8]. The information generated in the early discovery phase of metabolite identification can be used to identify lead compounds and undesirable metabolic products followed by optimization of pharmacokinetic and safety profiles. These metabolism studies are generally carried out by employing in vitro and in vivo systems [8] followed by using modern analytical techniques. Liquid chromatography-mass spectrometry (LC-MS) is the most popular and versatile analytical technique which has been widely used for the identification of trace levels of drugs and their metabolites in various biological matrices due to its high sensitivity [9][10][11][12]. Several strategies, such as MS/MS, MS n , on-line hydrogen/ deuterium exchange experiments, accurate mass measurements, softwares dedicated to the metabolite prediction (in silico tools), chemical derivatization and radio-labeling of parent drugs were used for structural characterization of metabolites [9][10][11][12][13][14][15].

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Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery

Cited by 411 publications

References 85 publications

Nanoparticle transport across the blood brain barrier

Nanoparticle transport across the blood brain barrier

The effect of neutral oximes on the reactivation of human acetylcholinesterase inhibited with paraoxon

Editorial: Drug Metabolism and Toxicology

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