1,720,982 research outputs found
Perspectives of Cannabinoid Type 2 Receptor (CB2R) Ligands in Neurodegenerative Disorders: Structure–Affinity Relationship (SAfiR) and Structure–Activity Relationship (SAR) Studies
Full text linkUp-regulation of CB2R on activated microglial cells, the first step in neurodegeneration, has been widely demonstrated, and this finding makes the receptor a promising target in the early diagnosis and treatment of several neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and multiple sclerosis (MS). The development of CB2R PET ligands could help demonstrate the neurodegenerative pathogenesis,
thus providing useful tools for characterizing the role of neuroinflammation in the progression of these disorders.
CB2R agonists and inverse agonists have emerged as neuroprotective agents, and CB2R agonists have entered several clinical trials. CB2R ligands have therefore received great attention, and different molecular scaffolds have been selected to target CB2R subtypes. This review is focused on structure−activity relationship (SAR) and structure−affinity relationship (SAfiR) studies performed on different scaffolds with the aim to identify the molecular features useful for the design of both therapeutic and diagnostic agents
HPLC-UV and LC-MS/MS analysis to study formulation and long-term stability of some anticancer drugs in elastomeric pumps
Full text linkDrug stability evaluations in elastomeric pump represent the first step to certify the safety of a therapeutic treatment in oncology. Since the stability of several anticancer molecules is due to their reactivity and stability in elastomeric pumps, made up of different materials, several experimental conditions, such as temperature, pH, concentration and possible chemical interactions among drugs in a single formulation, should be always investigated. Galenic preparation of anticancer drugs is an important prerogative of Anticancer Units within hospital pharmacies and, considering the burden of COVID-19 pandemic event, specific guidelines for therapeutic administration in elastomeric pumps reducing hospitalization both for post-surgical treatment and for therapeutic treatment have been worldwide elaborated. In the present study, the stability of Doxorubicin and Vincristine as a single formulation at different experimental conditions has been investigated. Moreover, we report a systematic study of 5-FU, which is known to be largely used in these medical devices, although its criticisms in terms of solubility, pH effect, storage time and conditions. Our results demonstrate that doxorubicin and vincristine can be mixed safely as a single formulation and 5-FU is stable for 32 days at different temperatures and concentrations in elastomeric pumps
Measurements of serum non-ceruloplasmin copper by a direct fluorescent method specific to Cu(II)
No full textBackground: Meta-analyses indicated the breakdown of copper homeostasis in the sporadic form of Alzheimer's disease (AD), comprising copper decreases within the brain and copper increases in the blood and the pool not bound to ceruloplasmin (non-Cp Cu, also known in the literature as "free" copper). The calculated non-Cp Cu (Walshe's) index has many limitations. Methods: A direct fluorescent method for non-Cp Cu detection has been developed and data are presented herein. The study included samples from 147 healthy subjects, 36 stable mild cognitive impairment (MCI) and 89 AD patients, who were tested for non-Cp Cu through the direct method, total serum copper, ceruloplasmin concentration and o-dianisidine ceruloplasmin activity. The indirect non-Cp Cu Walshe's index was also calculated. Results: The direct method was linear (0.9-5.9 mu M), precise (within-laboratory coefficient variation of 9.7% for low and 7.1% for high measurements), and had a good recovery. A reference interval (0-1.9 mu M) was determined parametrically in 147 healthy controls (27-84 years old). The variation of non-Cp Cu was evaluated according to age and sex. Non-Cp Cu was 1.5 times higher in AD patients (regarding the upper value of the reference interval) than in healthy controls. Healthy, MCI and AD subjects were differentiated through the direct non-Cp Cu method [areas under the curve (AUC) = 0.755]. Considering a 95% specificity and a 1.91 mu mol/L cut-off, the sensitivity was 48.3% (confidence interval 95%: 38%-58%). The likelihood ratio (LR) was 9.94 for positive test results (LR +) and 0.54 for negative test result (LR -). Conclusions: The direct fluorescent test reliably and accurately measures non-Cp Cu, thereby determining the probability of having AD. Keywords: Alzheimer's disease; ceruloplasmin; copper; metal; mild cognitive impairment; non-ceruloplasmin copper
In vitro and ex vivo characterization of sigma-1 and sigma-2 receptors: agonists and antagonists in biological assays.
No full textAn updated patent review on P-glycoprotein inhibitors (2011-2018)
No full textIntroduction: P-glycoprotein is a complex ATP-ase transporter involved in physiological and pathological
functions. In particular, it is involved in the onset of multidrug resistance in cancer, in ocular
disease, Chronic Rhinosinusitis, CNS diseases such as Alzheimer, Parkinson, and epilepsy. One of the
aims of clinicians and pharmacologists is to monitor P-gp activity through the inhibitors and to use its
activity and/or expression in physiological barriers for the early diagnosis of several pathologies.
Considering P-glycoprotein activity, several substrates have been characterized but the challenge is
to design ‘pure’ P-glycoprotein inhibitors.
Area covered: P-glycoprotein inhibitors display a large spectrum of activities. Here the contents of
patents focused on the role of P-glycoprotein inhibitor in modulating MDR in cancer, in bioavailability,
in ocular disease and Chronic Rhinosinusitis are reported.
Expert opinion: the use of P-glycoprotein inhibitor sic et simpliciter, or in coadministration with
therapeutic agents, for ocular disease, and Chronic Rhinosinusitis is promising and could be suggested
for additional trials. By contrast, the bioavailability of the coadministrated drugs, increased by
P-glycoprotein inhibitor, deserves a wider discussion, in particular on the pharmacokinetic aspect of
both P-glycoprotein inhibitor and the coadministered drug
Mixed 5-HT1A/D-2 activity of a new model of arylpiperazines: 1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines. 1. Synthesis and structure-activity relationships.
No full textSmall and innovative molecules as new strategy to revert MDR
No full textMultidrug resistance (MDR) is a complex phenomenon principally due to the overexpression of some transmembrane proteins belonging to the ATP binding cassette (ABC) transporter family. Among these transporters, P-glycoprotein (P-gp) is mostly involved in MDR and its overexpression is the major cause of cancer therapy failure. The classical approach used to overcome MDR is the co-administration of a P-gp inhibitor and the classic antineoplastic drugs, although the results were often unsatisfactory. Different classes of P-gp ligands have been developed and, among them, Tariquidar has been extensively studied both in vitro and in vivo. Although Tariquidar has been considered for several years as the lead compound for the development of P-gp inhibitors, recent studies demonstrated it to be a substrate and inhibitor, in a dose-dependent manner. Moreover, Tariquidar structure– activity relationship studies were difficult to carry out because of the complexity of the structure that does not allow establishing the role of each moiety for P-gp activity. For this purpose, SMALL molecules bearing different scaffolds such as tetralin, biphenyl, arylthiazole, furoxane, furazan have been developed. Many of these ligands have been tested both in in vitro assays and in in vivo PET studies. These preliminary evaluations lead to obtain a library of P-gp interacting agents useful to conjugate chemotherapeutic agents displaying reduced pharmacological activity and appropriate small molecules. These molecules could get over the limits due to the antineoplastic-P-gp inhibitor co-administration since pharmacokinetic and pharmacodynamic profiles are related to a dual innovative drug
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