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Journal of Medicinal Chemistry Jul 2021Epigenetic post-translational modifications are essential for human malaria parasite survival and progression through its life cycle. Here, we present new functionalized...
Epigenetic post-translational modifications are essential for human malaria parasite survival and progression through its life cycle. Here, we present new functionalized suberoylanilide hydroxamic acid (SAHA) derivatives that chemically combine the pan-histone deacetylase inhibitor SAHA with the DNA methyltransferase inhibitor procainamide. A three- or four-step chemical synthesis was designed starting from cheap raw materials. Compared to the single drugs, the combined molecules showed a superior activity in and a potent inhibition against human HDAC6, exerting no cytotoxicity in human cell lines. These new compounds are fully active in multidrug-resistant Cambodian isolates. They target transmission of the parasite by inducing irreversible morphological changes in gametocytes and inhibiting exflagellation. The compounds are slow-acting and have an additive antimalarial effect in combination with fast-acting epidrugs and dihydroartemisinin. The lead compound decreases parasitemia in mice in a severe malaria model. Taken together, this novel fused molecule offers an affordable alternative to current failing antimalarial therapy.
Topics: Antimalarials; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Hydroxamic Acids; Malaria, Falciparum; Molecular Structure; Plasmodium falciparum; Procainamide; Structure-Activity Relationship
PubMed: 34185525
DOI: 10.1021/acs.jmedchem.1c00821 -
Journal of Alzheimer's Disease : JAD 2021Memantine, an NMDA receptor antagonist, is used for the treatment of Alzheimer's disease. There is a caution to refrain from administrating memantine in combination with...
Safety of Memantine in Combination with Potentially Interactive Drugs in the Real World: A Pharmacovigilance Study Using the Japanese Adverse Drug Event Report (JADER) Database.
BACKGROUND
Memantine, an NMDA receptor antagonist, is used for the treatment of Alzheimer's disease. There is a caution to refrain from administrating memantine in combination with some specific drugs such as amantadine or dextromethorphan due to potential interactions that might augment the adverse effects of memantine.
OBJECTIVE
This notification has not been validated in real-world data, which we aim to address using a large self-reporting database from Japan.
METHODS
We conducted a disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database reported between April 2004 and March 2019 for detecting the neuropsychiatric adverse event (AE) signals associated with memantine and other potentially interactive drugs including amantadine, dextromethorphan, cimetidine, ranitidine, procainamide, quinidine, acetazolamide, citrate, and bicarbonate. Drug-drug interactions between memantine and these drugs were assessed using multiplicative and additive models.
RESULTS
There was no statistically robust evidence to support multiplicative or additive interactions between memantine and the aforementioned drugs to increase the reporting of any included neuropsychiatric AEs or AE categories.
CONCLUSION
The real-world JADER data did not raise the concern about the interactive increase in the neuropsychiatric AEs in patients with dementia taking memantine in combination with amantadine or dextromethorphan, suggesting there may be no urgent need to prohibit the co-administration of these drugs presently.
Topics: Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Alzheimer Disease; Databases, Factual; Drug Interactions; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Excitatory Amino Acid Antagonists; Female; Humans; Japan; Male; Memantine; Pharmacovigilance; Retrospective Studies
PubMed: 34151816
DOI: 10.3233/JAD-210524 -
Journal of Chromatography. A Aug 2021The advantages of using mixtures of organic solvents for the separation of labeled oligosaccharides on the amide stationary phase under hydrophilic interaction liquid...
Separation of labeled isomeric oligosaccharides by hydrophilic interaction liquid chromatography - the role of organic solvent in manipulating separation selectivity of the amide stationary phase.
The advantages of using mixtures of organic solvents for the separation of labeled oligosaccharides on the amide stationary phase under hydrophilic interaction liquid chromatography conditions are presented. The effect of the type of buffer as well as solvent or their mixtures on retention of uracil, saccharide labeling reagents (2-aminobenzoic acid, 2-aminobenzamide, ethyl 4-aminobenzoate, procainamide), and corresponding labeled saccharides were evaluated. The successful isocratic separation of labeled isomeric trisaccharides (maltotriose, panose, and isomaltotriose) was achieved in the mobile phase consisting of a 90% (v/v) mixture of organic solvents (methanol/acetonitrile 60:40) and 10% (v/v) 30 mM ammonium formate, pH 3.3. Changing the volume ratio between methanol/acetonitrile from 60:40 to 50:50 (v/v) allowed to obtain the separation of di-, tri-, and tetrasaccharides labeled by ethyl 4-aminobenzoate in less than 10.5 min.
Topics: Acetonitriles; Amides; Carbohydrates; Chemistry Techniques, Analytical; Chromatography, Liquid; Formates; Hydrophobic and Hydrophilic Interactions; Isomerism; Oligosaccharides; Solvents; ortho-Aminobenzoates
PubMed: 34147834
DOI: 10.1016/j.chroma.2021.462303 -
CJEM May 2021Acute atrial flutter has one-tenth the prevalence of acute atrial fibrillation in the emergency department (ED) but shares many management strategies. Our aim was to...
BACKGROUND
Acute atrial flutter has one-tenth the prevalence of acute atrial fibrillation in the emergency department (ED) but shares many management strategies. Our aim was to compare conversion from acute atrial flutter to sinus rhythm between pharmacological cardioversion followed by electrical cardioversion (Drug-Shock), and electrical cardioversion alone (Shock-Only).
METHODS
We conducted a randomized, blinded, placebo-controlled comparison of attempted pharmacological cardioversion with IV procainamide followed by electrical cardioversion if necessary, and placebo infusion followed by electrical cardioversion. We enrolled stable patients with a primary diagnosis of acute acute atrial flutter at 11 academic EDs. The primary outcome was conversion to normal sinus rhythm.
FINDINGS
From July 2013 to October 2018, we enrolled 76 patients, and none were lost to follow-up. Comparing the Drug-Shock to the Shock-Only group, conversion to sinus rhythm occurred in 33 (100%) versus 40 (93%) (absolute difference 7.0%; 95% CI - 0.6 to 14.6; P = 0.25). Median time to conversion from start of infusion in the Drug-Shock group was 24 min (IQR 21-82) but only 9 (27%) cases were converted with IV procainamide. Patients in both groups had similar outcomes at 14 days; there were no strokes or deaths.
INTERPRETATION
This trial found that the Drug-Shock strategy is potentially superior but that either approach to immediate rhythm control in the ED for patients with acute acute atrial flutter is highly effective, rapid, and safe in restoring sinus rhythm and allowing patients to go home and return to normal activities. Unlike the case of atrial fibrillation, we found that IV procainamide alone was infrequently effective.
Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Electric Countershock; Emergency Service, Hospital; Humans; Procainamide
PubMed: 33959925
DOI: 10.1007/s43678-020-00067-7 -
Cureus Apr 2021Myocardial ischemia may lead to lethal arrhythmias. Treatment of these arrhythmias without addressing the cause of ischemia may be futile. The length of resuscitation is...
BACKGROUND
Myocardial ischemia may lead to lethal arrhythmias. Treatment of these arrhythmias without addressing the cause of ischemia may be futile. The length of resuscitation is an important parameter for determining when to stop resuscitation but with shockable rhythms and reversible cause of the cardiac arrest, the decision to terminate resuscitation is complex. Case Summary: A patient with a three-month history of shortness of breath with effort developed pulseless ventricular tachycardia (VT) at the early stages of a stress test. In coronary angiography, a critical lesion in the right coronary artery (RCA) was observed and treated with two stents. During the procedure and for a total of five hours, the patient had more than 100 separate episodes of VT and ventricular fibrillation (VF) that were treated by 150 defibrillations, artificial ventilation, intra-aortic counter-pulsation balloon insertion, and multiple drugs. One hour after the initial stenting procedure, thrombosis of the RCA was demonstrated and treated successfully with angioplasty. Use of procainamide resolved the arrhythmias and the patient recovered completely without neurological deficit, ejection fraction of 45%, and is asymptomatic at one year following the event.
DISCUSSION
Our case shows that with a revisable cause of cardiac arrest, resuscitation should be directed at maintaining perfusion of essential organs and treating the reversible cause. Without re-opening the RCA, we could not have saved the patient's life. The use of an extracorporeal membrane oxygenator, if available, should be considered in similar cases. Finally, the quality of cardiopulmonary resuscitation determines the neurological outcome regardless of the length of resuscitation, as was evident in our patient who recovered completely.
PubMed: 33954068
DOI: 10.7759/cureus.14255 -
Methods in Molecular Biology (Clifton,... 2021The use of sequential exoglycosidase digestion of oligosaccharides followed by LC-FLD, LC-MS or CE analysis provides detailed carbohydrate structural information. Highly...
The use of sequential exoglycosidase digestion of oligosaccharides followed by LC-FLD, LC-MS or CE analysis provides detailed carbohydrate structural information. Highly specific exoglycosidases cleave monosaccharides from the nonreducing end of an oligosaccharide and yield information about the linkage, stereochemistry and configuration of the anomeric carbon. Here we use combinations of exoglycosidases to precisely characterize glycans on the Fc domain of therapeutic antibodies and dimeric fusion proteins. The workflow described includes glycan release with Rapid™ PNGase F (NEB #P0710), direct labeling of released glycans with procainamide (PCA) or 2-aminobenzamide (2AB), cleanup of labeled glycans and a 3 h enzymatic digestion with exoglycosidases. This protocol is designed for completion within an 8 h time frame to allow for subsequent LC-FLD, LC-MS, or CE analysis overnight.
Topics: Antibodies, Monoclonal; Carbohydrate Conformation; Chromatography, High Pressure Liquid; Fluorescent Dyes; Fluorometry; Glycoproteins; Glycoside Hydrolases; Glycosylation; Hydrolysis; Mass Spectrometry; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase; Polysaccharides; Procainamide; Protein Processing, Post-Translational; Recombinant Fusion Proteins; Research Design; Substrate Specificity; Workflow; ortho-Aminobenzoates
PubMed: 33908014
DOI: 10.1007/978-1-0716-1241-5_19 -
CJEM Jan 2021
Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Electric Countershock; Humans
PubMed: 33683610
DOI: 10.1007/s43678-020-00019-1 -
Diagnostics (Basel, Switzerland) Feb 2021In the last few years, cardiac magnetic resonance (CMR) imaging has progressively acquired a central role in the diagnosis and management of patients with ventricular...
In the last few years, cardiac magnetic resonance (CMR) imaging has progressively acquired a central role in the diagnosis and management of patients with ventricular arrhythmias (VA) [...].
PubMed: 33672729
DOI: 10.3390/diagnostics11020357 -
PLoS Neglected Tropical Diseases Feb 2021African sleeping sickness is caused by Trypanosoma brucei, a parasite transmitted by the bite of a tsetse fly. Trypanosome infection induces a severe transcriptional...
African sleeping sickness is caused by Trypanosoma brucei, a parasite transmitted by the bite of a tsetse fly. Trypanosome infection induces a severe transcriptional downregulation of tsetse genes encoding for salivary proteins, which reduces its anti-hemostatic and anti-clotting properties. To better understand trypanosome transmission and the possible role of glycans in insect bloodfeeding, we characterized the N-glycome of tsetse saliva glycoproteins. Tsetse salivary N-glycans were enzymatically released, tagged with either 2-aminobenzamide (2-AB) or procainamide, and analyzed by HILIC-UHPLC-FLR coupled online with positive-ion ESI-LC-MS/MS. We found that the N-glycan profiles of T. brucei-infected and naïve tsetse salivary glycoproteins are almost identical, consisting mainly (>50%) of highly processed Man3GlcNAc2 in addition to several other paucimannose, high mannose, and few hybrid-type N-glycans. In overlay assays, these sugars were differentially recognized by the mannose receptor and DC-SIGN C-type lectins. We also show that salivary glycoproteins bind strongly to the surface of transmissible metacyclic trypanosomes. We suggest that although the repertoire of tsetse salivary N-glycans does not change during a trypanosome infection, the interactions with mannosylated glycoproteins may influence parasite transmission into the vertebrate host.
Topics: Animals; Chromatography, Liquid; Concanavalin A; Glycoproteins; Glycoside Hydrolases; Insect Vectors; Lectins, C-Type; Polysaccharides; Saliva; Salivary Glands; Salivary Proteins and Peptides; Tandem Mass Spectrometry; Trypanosoma; Trypanosoma brucei brucei; Trypanosomiasis, African; Tsetse Flies
PubMed: 33529215
DOI: 10.1371/journal.pntd.0009071 -
Diagnostics (Basel, Switzerland) Jan 2021Acquiring high-quality cardiac magnetic resonance (CMR) images in patients with frequent ventricular arrhythmias remains a challenge. We examined the safety and efficacy...
Acquiring high-quality cardiac magnetic resonance (CMR) images in patients with frequent ventricular arrhythmias remains a challenge. We examined the safety and efficacy of procainamide when administered on the scanner table prior to CMR scanning to suppress ventricular ectopy and acquire high-quality images. Fifty consecutive patients (age 53.0 [42.0-58.0]; 52% female, left ventricular ejection fraction 55 ± 9%) were scanned in a 1.5 T scanner using a standard cardiac protocol. Procainamide was administered at intermittent intravenous bolus doses of 50 mg every minute until suppression of the ectopics or a maximum dose of 10 mg/kg. The average dose of procainamide was 567 ± 197 mg. Procainamide successfully suppressed premature ventricular contractions (PVCs) in 82% of patients, resulting in high-quality images. The baseline blood pressure (BP) was mildly reduced (mean change systolic BP -12 ± 9 mmHg; diastolic BP -4 ± 9 mmHg), while the baseline heart rate (HR) remained relatively unchanged (mean HR change -1 ± 6 bpm). None of the patients developed proarrhythmic changes. Bolus intravenous administration of procainamide prior to CMR scanning is a safe and effective alternative approach for suppressing PVCs and acquiring high-quality images in patients with frequent PVCs and normal or only mildly reduced systolic function.
PubMed: 33513676
DOI: 10.3390/diagnostics11020178