Current Pharmaceutical Design - Volume 28, Issue 14, 2022

Blood flow enables the delivery of oxygen and nutrients to the different tissues of the human body. Drugs follow the same route as oxygen and nutrients; thus, drug concentrations in tissues are highly dependent on the blood flow fraction delivered. Although the free drug concentration in blood correlates with pharmacodynamics, the pharmacodynamics of a drug is primarily commanded by the drug concentrations in the aqueous spaces of bodily tissues. However, the concentrations of the drug are not homogeneous throughout the tissues, and they rarely reflect the free drug concentration in the blood. This heterogeneity is due to differences in the blood flow fraction delivered to the tissues and membrane transporters, efflux pumps, and metabolic enzymes. The rate of drug elimination from the body (systemic elimination) depends more on the driving force of drug elimination than on the free concentration of the drug at the site from which the drug is being eliminated. In fact, the actual free drug concentration in the tissues results from the balance between the input and output rates. In the present paper, we develop a theoretical concept regarding solute partition between intravascular and extravascular spaces; discuss experimental research on aqueous/non-aqueous solute partitioning and clinical research on microdialysis; present hypotheses to predict in-vivo elimination using parameters of in-vitro metabolism.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease of growing interest given that there is cognitive damage and symptom onset acceleration. Therefore, it is important to find AD biomarkers for early diagnosis, disease progression, and discrimination of AD and other diseases. Objective: The objective of this study is to update the relevance of mass spectrometry for the identification of peptides and proteins involved in AD useful as discriminating biomarkers. Methods: Proteomics and peptidomics technologies that show the highest possible specificity and selectivity for AD biomarkers are analyzed, together with the biological fluids used. In addition to positron emission tomography and magnetic resonance imaging, MALDI-TOF mass spectrometry is widely used to identify proteins and peptides involved in AD. The use of protein chips in SELDI technology and electroblotting chips for peptides makes feasible small amounts (μL) of samples for analysis. Results: Suitable biomarkers are related to AD pathology, such as intracellular neurofibrillary tangles; extraneuronal senile plaques; neuronal and axonal degeneration; inflammation and oxidative stress. Recently, peptides were added to the candidate list, which are not amyloid-β or tau fragments, but are related to coagulation, brain plasticity, and complement/neuroinflammation systems involving the neurovascular unit. Conclusion: The progress made in the application of mass spectrometry and recent chip techniques is promising for discriminating between AD, mild cognitive impairment, and matched healthy controls. The application of this technique to blood samples from patients with AD has shown to be less invasive and fast enough to determine the diagnosis, stage of the disease, prognosis, and follow-up of the therapeutic response.

Background: Alzheimer´s disease (AD) is the most widespread dementia in the world, followed by vascular dementia. Since AD is a heterogeneous disease that shows several varied phenotypes, it is not easy to make an accurate diagnosis, so it arises when the symptoms are clear and the disease is already at an advanced stage. Therefore, it is important to find out biomarkers for early AD diagnosis that facilitate treatment or slow down the disease. Classic biomarkers are obtained from cerebrospinal fluid and plasma, along with brain imaging by positron emission tomography. Attempts have been made to discover uncommon biomarkers from other body fluids, which are addressed in this update. Objective: This update aims to describe recent biomarkers from minimally invasive body fluids for the patients, such as saliva, urine, eye fluid or tears. Methods: Biomarkers were determined in patients versus controls by single tandem mass spectrometry and immunoassays. Metabolites were identified by nuclear magnetic resonance and microRNAs with genome-wide high-throughput real-time polymerase chain reaction-based platforms. Results: Biomarkers from urine, saliva, and eye fluid were described, including peptides/proteins, metabolites, and some microRNAs. The association with AD neuroinflammation and neurodegeneration was analyzed, highlighting the contribution of matrix metalloproteinases, the immune system and microglia, as well as the vascular system. Conclusion: Unusual biomarkers have been developed, which distinguish each stage and progression of the disease, and are suitable for the early AD diagnosis. An outstanding relationship of biomarkers with neuroinflammation and neurodegeneration was assessed, clearing up concerns about the etiopathogenesis of AD.

Biomarkers capable of identifying and distinguishing types of dementia, such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), Lewy body dementia (LBD), and frontotemporal dementia (FTD), have become increasingly relentless. Studies on possible biomarker proteins in the blood that can help formulate new diagnostic proposals and therapeutic visions of different types of dementia are needed. However, due to several limitations of these biomarkers, especially in discerning dementia, their clinical applications are still undetermined. Thus, updating biomarker blood proteins that can help in the diagnosis and discrimination of these main dementia conditions is essential to enable new pharmacological and clinical management strategies with specificities for each type of dementia. This paper aimed to review the literature concerning protein bloodbased AD and non-AD biomarkers as new pharmacological targets and/or therapeutic strategies. Recent findings related to protein-based AD, PDD, LBD, and FTD biomarkers are focused on in this review. Protein biomarkers are classified according to the pathophysiology of the dementia types. The diagnosis and distinction of dementia through protein biomarkers is still a challenge. The lack of exclusive biomarkers for each type of dementia highlights the need for further studies in this field. Only after this, blood biomarkers may have a valid use in clinical practice as they are promising to help in the diagnosis and in the differentiation of diseases.

Background: Ischemic stroke produces a large health impact worldwide, with scarce therapeutic options. Objective: This study aimed to reveal the role of NADPH oxidase and neuroinflammatory genes in the cerebral anti-ischemic effects of C-Phycocyanin (C-PC), the chief biliprotein of Spirulina platensis. Methods: Rats with either focal cerebral ischemia/reperfusion (I/R) or acute brain hypoperfusion, received C-PC at different doses, or a vehicle, for up to 6 h post-stroke. Neurological, behavioral and histochemical parameters were assessed in I/R rats at 24 h. Cerebral gene expression and hippocampal neuron viability were evaluated in hypoperfused rats at acute (24 h) or chronic phases (30 days), respectively. A molecular docking analysis of NOX2 and C-PC-derived Phycocyanobilin (PCB) was also performed. Results: C-PC, obtained with a purity of 4.342, significantly reduced the infarct volume and neurological deficit in a dose-dependent manner, and improved the exploratory activity of I/R rats. This biliprotein inhibited NOX2 expression, a crucial NADPH oxidase isoform in the brain, and the superoxide increase produced by the ischemic event. Moreover, C-PC-derived PCB showed a high binding affinity in silico with NOX2. C-PC downregulated the expression of pro-inflammatory genes (IFN-γ, IL-6, IL-17A, CD74, CCL12) and upregulated immune suppressive genes (Foxp3, IL-4, TGF-β) in hypoperfused brain areas. This compound also decreased chronic neuronal death in the hippocampus of hypoperfused rats. Conclusion: These results suggest that the inhibition of cerebral NADPH oxidase and the improvement of neuroinflammation are key mechanisms mediating the neuroprotective actions of C-PC against brain ischemia.

Background: Focal epilepsies have been described as a network disease. Noninvasive investigative techniques have been used to characterize epileptogenic networks. Objective: This study aimed to describe ictal and interictal cortical and subcortical perfusion patterns using single- photon emission computed tomography (SPECT) in patients with drug-resistant epilepsy (DRE). Methods: Thirty-five interictal-ictal SPECT scans were obtained from 15 patients with DRE. A methodology was developed to get a relative perfusion index (PI) of 74 cortical and sub-cortical brain structures. K-means algorithm, together with modified v-fold cross-validation, was used to identify the two regions of interest (ROIs) that represent hypoperfused and hyperperfused areas. Results: In common with the individual analysis, the statistical analysis evidenced that the hyperperfusion ROIs resulting from group analysis during interictal and ictal involved mainly the cingulate gyrus, cuneus, lingual gyrus, and gyrus rectus as well as the putamen. ROIs hypoperfused included the red nucleus, the substantia nigra, and the medulla. The medians of the group analysis of the hypoperfusion and hyperperfusion ROIs were 0.601-0.565 and 1.133-1.119 for the ictal and interictal states, correspondingly. A group of mostly cortical structures involved in the hyperperfused ROIs in both interictal and ictal states showed no change or negative change in the transition from interictal to ictal state (mean change of -0.002). On the other hand, the brain stem, basal ganglia, red nucleus, and thalamus revealed a mean global change of 0.19, indicating a mild increase in the PI. However, some of these structures (red nucleus, substantia nigra, and medulla oblongata) remained hypoperfused during the interictal to ictal transition. Conclusion: The methodology employed made it possible to identify common cortical and subcortical perfusion patterns not directly linked to epileptogenicity, for a better epileptogenic network and sudden unexpected death (SUDEP) mechanism in DRE.