- Recent Progress in Construction of Natural De-O-sulfonated Sulfonium Sugars with Antidiabetic Activities. [Journal Article]
- CChemistry 2019 Jul 17
- A group of sulfonium salts equipped with a poly hydroxylated side chain structure have been isolated and identified as potent alpha-glycosidase inhibitors. Consequently, they became attractive target…
A group of sulfonium salts equipped with a poly hydroxylated side chain structure have been isolated and identified as potent alpha-glycosidase inhibitors. Consequently, they became attractive target in diverse research disciplines including organic synthesis, drug discovery and chemical biology. To this end, the development practical and effective synthetic strategies especially for more bioactive de-Osulfonated sulfonium salts is one of significant research areas in organic synthesis. An ideal synthetic methodology should provide easily accessible intermediates with high chemical stability for the key coupling reaction to diastereoselectively construct sulfonium cation center. This minireview summarized the recent developed strategies that applied in the construction of natural de-O-sulfonated sulfonium sugars: A) coupling reaction between cyclic sulfate and thiosugar, B) coupling reaction between side chain fragments containing leaving groups and thiosugar, C) coupling reaction between side chain fragments containing epoxide structures and thiosugar, D) a two step sequential SN2 nucleophilic substitution between side chain fragments containing thiol groups and a diiodide derivative.
- Tailoring the Chemical Modification of Chitosan Hydrogels to Fine Tune the Release of a Synergistic Combination of Chemotherapeutics. [Journal Article]
- BBiomacromolecules 2019 Jul 16
- Combination chemotherapy with defined ratio and sequence of drug release is a clinically established and effective route to treat advanced solid tumors. In this context, a growing body of literature …
Combination chemotherapy with defined ratio and sequence of drug release is a clinically established and effective route to treat advanced solid tumors. In this context, a growing body of literature demonstrates the potential of hydrogels constructed with chemically modified polysaccharides as depots for controlled release of chemotherapeutics. Identifying the appropriate modification in terms of physicochemical properties of the functional group and its degree of substitution (χ) to achieve the desired release profile for multiple drugs is, however, a complex multivariate problem. To address this issue, we have developed a computational toolbox that models the migration of a drug pair through a hydrated network of polysaccharide chains modified with hydrophobic moieties. In this study, we chose Doxorubicin (DOX) and Gemcitabine (GEM) as model drugs, as their synergistic effect against breast cancer has been thoroughly investigated, and chitosan as model polymer. Our model describes how the modification of chitosan chains with acetyl, butanoyl, and heptanoyl moieties at different values χ governs both the structure of the hydrogel network and drug migration through it. Our experimental data confirm the in silico predictions for both single and dual-drug release, and, most notably, the counterintuitive inversion of release vs. χ that occurs when switching from a single to a dual-drug system. Consensus between predicted and experimental data indicates that acetyl modifications (χ = 32-42%) and butanoyl-modifications (χ = 19-24%) provide synergistic GEM/DOX release molar ratios (5-10 i.e.,). Collectively, these results demonstrate the potential of this model in guiding the design of chemotherapeutic hydrogels to combat cancer.
- Generation of Aryl Radicals from Aryl Halides: Rongalite-Promoted Transition-Metal-Free Arylation. [Journal Article]
- JOJ Org Chem 2019 Jul 16
- A new and practical method for the generation of aryl radicals from aryl halides is reported. Rongalite as a novel precursor of super electron donors was used to initiate a series of electron-catalyz…
A new and practical method for the generation of aryl radicals from aryl halides is reported. Rongalite as a novel precursor of super electron donors was used to initiate a series of electron-catalyzed reactions under mild conditions. These transition-metal-free radical chain reactions enable the efficient formation of C-C, C-S and C-P bond through homolytic aromatic substitution or SRN1 reactions. Moreover, the synthesis of antipsychotic drug Quetiapine was performed on gram scale through the described method. This protocol demonstrated its potential as a promising arylation method in organic synthesis.
- Renal Function Estimates and Dosing of Direct Oral Anticoagulants in Stroke Patients with Atrial Fibrillation: An Observational Study. [Journal Article]
- ANActa Neurol Taiwan 2018 Jun 15; 27(2):39-44
- CONCLUSIONS: Although substituting eGFR for CrCl carries potential risks of DOAC overdosing in patients with AF, the effect might be offset by clinicians' predilection for lower dosage in this stroke cohort.
- An intervention to improve HCV testing, linkage to care, and treatment among people who use drugs in Tehran, Iran: The ENHANCE study. [Journal Article]
- IJInt J Drug Policy 2019 Jul 11
- CONCLUSIONS: Following on-site HCV testing and linkage to care, HCV treatment uptake was extremely high among PWUD, apart from the homeless reception population. This intervention could be explored in other settings globally to enhance HCV scale-up and elimination efforts.
- Monitoring opioid addiction and treatment: Do you know if your population is engaged? [Journal Article]
- DADrug Alcohol Depend 2019 Jul 06; 202:56-60
- CONCLUSIONS: A health-system level view of the continuum of opioid addiction care identified improvement opportunities to better monitor accuracy of diagnosis, treatment capacity, and effectiveness of patient engagement. Applied longitudinally at local, state and national levels, the model could better synergize responses to the opioid crisis.
- Molecular surveillance of putative drug resistance markers of antifolate and artemisinin among imported Plasmodium falciparum in Qatar. [Journal Article]
- PGPathog Glob Health 2019 Jul 12; :1-9
- Malaria remains a significant public health challenge and is of global importance. Imported malaria is a growing problem in non-endemic areas throughout the world and also in Qatar due to a massive i…
Malaria remains a significant public health challenge and is of global importance. Imported malaria is a growing problem in non-endemic areas throughout the world and also in Qatar due to a massive influx of migrants from endemic countries. Antimalarial drug resistance is an important deterrent in our fight against malaria today. Molecular markers mirror intrinsic antimalarial drug resistance and their changes precede clinical resistance. Thus, in the present study, molecular markers of sulphadoxine-pyrimethamine (Pfdhfr and Pfdhps) and artemisinin (PfATPase6 and Pfk13) were sequenced to determine the drug resistance genotypes among 118 imported P. falciparum isolates in Qatar, between 2013 and 2016. All the isolates had mutant Pfdhfr alleles, with either double mutant (51I/108N) (59.3%) or triple mutant (51I, 59R and 108N) (30.6%) genotypes. I164L substitution was not found in this study. In case of Pfdhps, majority of the samples were carriers of either single (S436A/ A437G/ K540E) mutant (47.2%) or double (S436A/K540E, A437G/K540E, K540E/A581G) mutant (39.8%). A single novel point mutation (431V) was observed in the samples originated from Nigeria and Ghana. Polymorphisms in PfATPase6 were absent and only one non-synonymous mutation in Pfk13 was found at codon G453A from a sample of Kenyan origin. High levels of sulphadoxine-pyrimethamine resistance in the present study provide potential information about the spread of antimalarial drug resistance and will be beneficial for the treatment of imported malaria cases in Qatar.
- [3 + 2]-Annulation of Azaoxyallyl Cations and Thiocarbonyls for the Assembly of Thiazolidin-4-ones. [Journal Article]
- OLOrg Lett 2019 Jul 11
- A base-promoted, efficient [3 + 2] annulation between azaoxyallyl cations and thiocarbonyls is reported for flexible access to highly functionalized thiazolidin-4-one derivatives in good to excellent…
A base-promoted, efficient [3 + 2] annulation between azaoxyallyl cations and thiocarbonyls is reported for flexible access to highly functionalized thiazolidin-4-one derivatives in good to excellent yields. An intriguing feature of this method is the metal or Lewis acid free late-stage entry of distinct set of functional groups at C2 of thiazolidin-4-ones via substitution of a latent amino functional group. Overall, this approach constitutes a general platform for convenient access to this medicinally important scaffold.
- Using pharmacokinetics for tailoring prophylaxis in people with hemophilia switching between clotting factor products: A scoping review. [Review]
- RPRes Pract Thromb Haemost 2019; 3(3):528-541
- The objective of this scoping review is to summarize the current use of pharmacokinetics for tailoring prophylaxis in hemophilia patients switching between clotting factor products. Patients with hem…
The objective of this scoping review is to summarize the current use of pharmacokinetics for tailoring prophylaxis in hemophilia patients switching between clotting factor products. Patients with hemophilia may require switching of clotting factor concentrates due to a variety of factors, but there have been perceived risks associated with switching, such as inhibitor development or suboptimal protection due to inadequate dosing while titrating treatment. Studies that look at patients switching from one clotting factor concentrate to another are categorized in terms of their primary and/or secondary objectives, notably biosimilarity and comparative pharmacokinetic studies and inhibitor development studies. Research on how best to switch concentrates with respect to dosing regimen are lacking, and currently a trial-and-error approach is used for dosing the new factor concentrate. In the future, studies looking at the predictability of pharmacokinetics (PK) of a new factor concentrate based on individual PK knowledge of the original factor concentrate may offer clinical benefit by providing a safer switching approach and protocol.
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- Dopaminergic modulation of motor network compensatory mechanisms in Parkinson's disease. [Journal Article]
- HBHum Brain Mapp 2019 Jul 10
- The dopaminergic system has a unique gating function in the initiation and execution of movements. When the interhemispheric imbalance of dopamine inherent to the healthy brain is disrupted, as in Pa…
The dopaminergic system has a unique gating function in the initiation and execution of movements. When the interhemispheric imbalance of dopamine inherent to the healthy brain is disrupted, as in Parkinson's disease (PD), compensatory mechanisms act to stave off behavioral changes. It has been proposed that two such compensatory mechanisms may be (a) a decrease in motor lateralization, observed in drug-naïve PD patients and (b) reduced inhibition - increased facilitation. Seeking to investigate the differential effect of dopamine depletion and subsequent substitution on compensatory mechanisms in non-drug-naïve PD, we studied 10 PD patients and 16 healthy controls, with patients undergoing two test sessions - "ON" and "OFF" medication. Using a simple visually-cued motor response task and fMRI, we investigated cortical motor activation - in terms of laterality, contra- and ipsilateral percent BOLD signal change and effective connectivity in the parametric empirical Bayes framework. We found that decreased motor lateralization persists in non-drug-naïve PD and is concurrent with decreased contralateral activation in the cortical motor network. Normal lateralization is not reinstated by dopamine substitution. In terms of effective connectivity, disease-related changes primarily affect ipsilaterally-lateralized homotopic cortical motor connections, while medication-related changes affect contralaterally-lateralized homotopic connections. Our findings suggest that, in non-drug-naïve PD, decreased lateralization is no longer an adaptive cortical mechanism, but rather the result of maladaptive changes, related to disease progression and long-term dopamine replacement. These findings highlight the need for the development of noninvasive therapies, which would promote the adaptive mechanisms of the PD brain.