Can 24 h of ambulatory ECG be used to triage patients to extended monitoring?

BACKGROUND: Access to long-term ambulatory recording to detect atrial fibrillation (AF) is limited for economical and practical reasons. We aimed to determine whether 24 h ECG (24hECG) data can predict AF detection on extended cardiac monitoring. METHODS: We included all US patients from 2020, aged 17-100 years, who were monitored for 2-30 days using the PocketECG device (MEDICALgorithmics), without AF ≥30 s on the first day (n = 18,220, mean age 64.4 years, 42.4% male). The population was randomly split into equal training and testing datasets. A Lasso model was used to predict AF episodes ≥30 s occurring on days 2-30. RESULTS: The final model included maximum heart rate, number of premature atrial complexes (PACs), fastest rate during PAC couplets and triplets, fastest rate during premature ventricular couplets and number of ventricular tachycardia runs ≥4 beats, and had good discrimination (ROC statistic 0.7497, 95% CI 0.7336-0.7659) in the testing dataset. Inclusion of age and sex did not improve discrimination. A model based only on age and sex had substantially poorer discrimination, ROC statistic 0.6542 (95% CI 0.6364-0.6720). The prevalence of observed AF in the testing dataset increased by quintile of predicted risk: 0.4% in Q1, 2.7% in Q2, 6.2% in Q3, 11.4% in Q4, and 15.9% in Q5. In Q1, the negative predictive value for AF was 99.6%. CONCLUSION: By using 24hECG data, long-term monitoring for AF can safely be avoided in 20% of an unselected patient population whereas an overall risk of 9% in the remaining 80% of the population warrants repeated or extended monitoring.

Diagnostic yield of ambulatory cardiac monitoring in pediatric patients with palpitations.

Background: Palpitations are a frequent reason for referral to pediatric cardiology providers and diagnostic workup includes ambulatory cardiac monitoring. While common practice, the diagnostic yield is unknown in the pediatric population. The objective is to evaluate the diagnostic yield of 24-h Holter and extended ambulatory cardiac monitoring in pediatric patients with palpitations. Methods and Results: All pediatric patients aged 10-18 years who had ambulatory cardiac monitoring (1-30 days) through the Pocket Electrocardiogram (PocketECG™) system (Medi-Lynx) between January 2016 and July 2020 were included. Patients with an International Classification of Diseases-10 diagnosis code of palpitations (R00.2) during enrollment were evaluated separately. Tachyarrhythmia diagnoses included atrial fibrillation (AF), nonsustained supraventricular tachycardia (nSVT), supraventricular tachycardia (SVT), nonsustained ventricular tachycardia (nVT), and ventricular tachycardia (VT). Age, heart rates, arrhythmia type, and symptomatic transmission data were collected and analyzed. A total of 2388 patients (mean age 11.6 years, 58% F) with the R00.2 code had ambulatory cardiac monitoring (28% 24-h Holter, 72% extended) performed during the study period and there were 6287 total patients (mean age 13.9 years, 54% F) that underwent ambulatory cardiac monitoring (42% 24-h Holter, 58% extended) during that time. Of 2388 patients, 321 (13%) were diagnosed with tachyarrhythmia: AF (9), nSVT (192), SVT (59), and nVT (61). In the overall cohort, 764 (12%) patients were diagnosed with tachyarrhythmia: AF (22), nSVT (478), SVT (85), nVT (177), and VT (2). Symptomatic transmissions with normal cardiac rhythm were common in the R00.2 (n = 1697, 71%) and overall (n = 3848, 61%) groups. No episodes of nSVT, SVT, nVT, or VT were associated with symptomatic transmissions. Conclusion: Ambulatory cardiac monitors are an integral part of the diagnostic workup for pediatric palpitations patients and have demonstrated a high yield of combined positive arrhythmia diagnoses and symptomatic normal transmissions. Further prospective study of this population with the integration of clinical information is warranted.

Ventricular tachycardia risk prediction with an abbreviated duration mobile cardiac telemetry.

Background: Ventricular tachycardia (VT) occurs intermittently, unpredictably, and has potentially lethal consequences. Objective: Our aim was to derive a risk prediction model for VT episodes ≥10 beats detected on 30-day mobile cardiac telemetry based on the first 24 hours of the recording. Methods: We included patients who were monitored for 2 to 30 days in the United States using full-disclosure mobile cardiac telemetry, without any VT episode ≥10 beats on the first full recording day. An elastic net prediction model was derived for the outcome of VT ≥10 beats on monitoring days 2 to 30. Potential predictors included age, sex, and electrocardiographic data from the first 24 hours: heart rate; premature atrial and ventricular complexes occurring as singlets, couplets, triplets, and runs; and the fastest rate for each event. The population was randomly split into training (70%) and testing (30%) samples. Results: In a population of 19,781 patients (mean age 65.3 ± 17.1 years, 43.5% men), with a median recording time of 18.6 ± 9.6 days, 1510 patients had at least 1 VT ≥10 beats. The prediction model had good discrimination in the testing sample (area under the receiver-operating characteristic curve 0.7584, 95% confidence interval 0.7340-0.7829). A model excluding age and sex had an equally good discrimination (area under the receiver-operating characteristic curve 0.7579, 95% confidence interval 0.7332-0.7825). In the top quintile of the score, more than 1 in 5 patients had a VT ≥10 beats, while the bottom quintile had a 98.2% negative predictive value. Conclusion: Our model can predict risk of VT ≥10 beats in the near term using variables derived from 24-hour electrocardiography, and could be used to triage patients to extended monitoring.

Clinical outcomes in patients with acute myocardial infarction treated with primary percutaneous coronary intervention stratified according to duration of pain-to-balloon time and type of myocardial infarction.

BACKGROUND: Based on the clinical outcomes of patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), treated with primary percutaneous coronary intervention (pPCI), this study intended to assess mortality and major adverse cardiac and cerebrovascular event (MACCE) rates according to duration of pain-to-balloon (PTB) time and type of MI. METHODS: This is a retrospective cohort study based on the prospectively collected ORPKI registry which covers PCIs performed in Poland chosen between January 2014 and December 2017. Under assessment were 1,994 STEMI and 923 NSTEMI patients. Study endpoints included mortality and MACCE rates (in-hospital, 30-day, 12- and 36-month). Predictors of all-cause mortality in the overall group, STEMI and NSTEMI were assessed by multivariable analysis. RESULTS: Kaplan-Meier survival curve analysis did not reveal significant differences between the STEMI and NSTEMI group for all-cause mortality or MACCE at the 36-month follow-up. While in the long PTB time group, MACCE rate was significantly greater in STEMI patients when compared to NSTEMI (p = 0.004). Among STEMI patients, the short, medium and long PTB time groups differed significantly in the rate of all-cause mortality (p = 0.006) and MACCE (p = 0.04) at 1,095 days of follow-up, which were the greatest in the long PTB time group. CONCLUSIONS: Before considering the length of PTB time, there were no statistically significant differences in mortality or MACCE frequency between the STEMI and NSTEMI group at 36-month follow-up. Longer PTB times are related to significantly greater mortality at the 36-month follow-up in the STEMI, but not in the NSTEMI group.

When Peppa Pig and Confucius meet, joining forces on the battlefield of health literacy-a qualitative analysis of COVID-19 educational materials for children and adolescents from China, the USA, and Europe.

In times of pandemic, health literacy (HL) is very important, as it helps to find, understand, and use essential health information and services. According to WHO, HL is pivotal in fighting infodemic effectively, and education is a vital tool for developing it. In the presented work, we analyze 247 educational materials dedicated to children, adolescents, and their carers explaining the pandemic, prepared by the Chinese, American, German, Italian and Polish governments and international non-governmental organizations. Focusing on the textual and visual side of the documents, we investigated how the pandemic is explained and what discursive measures were used to inform young citizens about the risks and consequences of pandemic restrictions. Additionally, we verified whether the materials helped developing critical thinking, which is crucial to prevent spreading fake news and conspiracy theories. Although the analyzed materials were prepared in different cultural contexts, we identified that all of them contained simple instructions on the desired behaviours during the pandemic. Key messages relating to the importance of hygienic behaviors were often supplemented with guidelines on how to successfully complete each action. While the cultural particularities in presenting the state of the pandemic are visible, the challenges of dealing with the emotional and social crises were dominant all around the world. In our study, we argue that the possibilities of building HL were not fully exploited by the national and international institutions. Citizens were taught how to behave in unusual circumstances but not why they should behave differently. The educational materials lacked reliable knowledge that would allow them to deal with infodemic and develop critical thinking. We conclude that health education expertise worldwide should be focused on enhancing individuals' ability to make informed health decisions and provide three recommendations regarding the process of development of health educational resources for children and the youth.

Diabetes Mellitus Is Still a Strong Predictor of Periprocedural Outcomes of Primary Percutaneous Coronary Interventions in Patients Presenting with ST-Segment Elevation Myocardial Infarction (from the ORPKI Polish National Registry).

The impact of diabetes mellitus (DM) on outcomes of patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) was confirmed by several studies. However, it is unclear whether this effect is still present in large groups of unselected patients undergoing up-to-date treatment. Thus, we sought to assess the impact of DM on periprocedural outcomes of primary PCI in STEMI using data from the Polish National Registry of PCI. Data on 150,782 STEMI patients undergoing primary PCI were collected. Of them, 26,360 (17.5%) patients had DM. Patients with DM were higher-risk individuals who experienced longer reperfusion delays and were less likely to have closed infarct-related artery at baseline (TIMI 0 + 1 flow: 73.2% vs. 72.0%; p < 0.0001) and achieve optimal reperfusion after PCI (TIMI 3 flow: 91.8% vs. 88.5%; p < 0.0001). The periprocedural mortality (1.1% vs. 1.9%; p < 0.0001) was higher in patients with DM and DM was identified as an independent predictor of periprocedural death. In conclusion, despite continuous progress in STEMI treatment, DM remains a strong predictor of periprocedural mortality. However, this detrimental effect of DM may be partially explained by the overall higher risk profile of diabetic patients.

Ambulatory Cardiac Monitoring in Infants with Supraventricular Tachycardia.

Supraventricular tachycardia (SVT) is a frequent cause of tachyarrhythmia in infants < 1 year of age and ambulatory cardiac monitoring is an important tool for diagnosis and follow-up of these patients. We retrospectively reviewed 594 infants (mean age 4.05 months, SD 3.55; 54% M) who underwent ambulatory cardiac monitoring (69% 24 h Holter, 31% extended monitor) through the Pocket ECG system (MediLynx) between January 2016 and July 2020. 170 patients who had the ICD-10 code I47.1 for SVT used at enrollment were analyzed separately. 49 (8.3%) patients had sustained SVT or non-sustained SVT (nSVT) during the study period, including 20 patients (11.8%) who had the ICD-10 code I47.1 at enrollment. Extended ambulatory cardiac monitors detected 61% of all patients with nSVT or SVT and was superior when compared to 24 h Holter (p < 0.0001). In the overall group, the first episode of SVT or nSVT was detected within 24 h of monitoring in 40/49 patients (82%). 48/49 patients (98%) were diagnosed within a week of monitoring and the single remaining patient was diagnosed with nSVT at day 15 of monitoring. There was no significant difference in minimal, maximal, and average heart rate between patients with and without ICD-10 code I47.1 at enrollment or between patients with and without SVT or nSVT. Despite their low yield, ambulatory cardiac monitors are an important diagnostic tool. The ideal length of monitoring in patients with known or suspected SVT has yet to be defined, although all patients in our cohort were identified by day 15 of monitoring.

Sex differences in presentation of atrial fibrillation: Findings from 30-day ambulatory monitoring in real-world practice.

Background: Women are less likely to receive oral anticoagulation or ablation for treatment of atrial fibrillation (AF). Identification of sex differences in arrhythmia characteristics and symptoms may lead to a better understanding of potential reasons for these differences. Objectives: To determine sex differences in AF with respect to heart rate, duration, burden, and symptoms in patients undergoing mobile cardiac telemetry (MCT) monitoring. Methods: All patients who registered for ≤30-day MCT using PocketECG (MediLynx) in the USA in 2017 were included (n = 27,512, 58 % women). PocketECG records and transmits a three-lead ambulatory electrocardiogram (ECG) with real-time beat-to-beat analysis. Sex-related differences were analyzed with Chi2 and Spearmans rho. Results: Fewer women than men were diagnosed with AF lasting ≥30s (13.7 % versus [vs] 19.0 %, p < 0.001). AF burden was lower in women in all age groups <90 years (all p < 0.01). Women were older at the time of AF diagnosis (median 76 vs 73 years, p < 0.001), had faster heart rate during AF (mean: 104.7 ± 26.0 vs 96.7 ± 26.7 bpm, p < 0.001), and shorter AF duration (mean: 96.2 ± 176.0 vs 121.6 ± 189.9 min, p < 0.001). There was a non-significant trend toward more symptoms (such as dizziness, racing heart, fatigue, or palpitations) during AF in women compared to men (46.5 % vs 43.7 %, p = 0.062). Conclusions: AF was less prevalent and occurred at lower burdens in women than men in each age strata. Despite faster heart rates in AF in women, there were no significant sex differences in reported symptoms during AF. Sex differences in therapy cannot be explained by differences in symptoms or rates in AF. Condensed abstract: Real-world data on sex differences in AF using a 30-day MCT monitoring device remain scarce. We aim to determine the sex differences in AF with respect to prevalence, burden, heart rate, and symptom in patients undergoing ≤30-day MCT monitoring. Our data analysis suggests that fewer women than men had AF, women were older at diagnosis of AF, and women with AF had higher mean heart rate, shorter mean AF duration, and lower mean AF burden than men. Further studies are needed to examine reasons for sex differences, specifically in relation to AF therapy and its impact on clinical outcomes.

Assessment of application of the new 2019 European Society of Cardiology/ European Atherosclerosis Society Guidelines for the Management of Dyslipidaemias in daily clinical practice - one center study.

B a c k g r o u n d: Cardiovascular diseases are the first cause of death globally. Hypercholester- olemia is the most important factor responsible for atherosclerotic plaque formation and increasing cardiovascular risk. Reduction of LDL-C level is the most relevant goal for reduction of cardiovascular risk. A i m s: Real life adherence to guidelines concerning statin therapy in one center study population. M e t h o d s: We analyzed data collected in the Department of Internal Diseases from September 2019 to February 2020, obtained from 238 patients hospitalized in this time period. We assessed application of the new 2019 ESC/EAS Guidelines for the Management of Dyslipidaemias in daily clinical practice and compared effectiveness of LLT according to 2016 and 2019 guidelines. R e s u l t s: Only 1 in 5 patients with dyslipideamia achieve the 2019 ESC/EAS guideline-recommended levels of LDL-C with relation to their TCVR. We noticed that 20 of patients who did not achieve proper 2019 LDL level, meet new therapy targets established in year 2016. We observed that higher patient TCVR resulted in better compliance with guidelines and ordination of proper LLT. Most patients were on monotherapy with statins. C o n c l u s i o n s: It could be beneficial to start treatment with double or even triple therapy especially in group with the highest LDL-C levels.

Manifestation of Susac syndrome during interferon beta-1a and glatiramer acetate treatment for misdiagnosed multiple sclerosis: a case report.

BACKGROUND: Susac syndrome (SS) is characterized by the triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss. However, the diagnosis of SS remains difficult because the clinical triad rarely occurs at disease onset, and symptom severity varies. SS symptoms often suggest other diseases, in particular multiple sclerosis (MS), which is more common. Misdiagnosing SS as MS may cause serious complications because MS drugs, such as interferon beta-1a, can worsen the course of SS. This case report confirms previous reports that the use of interferon beta-1a in the course of misdiagnosed MS may lead to exacerbation of SS. Moreover, our case report shows that glatiramer acetate may also exacerbate the course of SS. To the best of our knowledge, this is the first reported case of exacerbation of SS by glatiramer acetate. CASE PRESENTATION: We present a case report of a patient with a primary diagnosis of MS who developed symptoms of SS during interferon beta-1a treatment for MS; these symptoms were resolved after the discontinuation of the treatment. Upon initiation of glatiramer acetate treatment, the patient developed the full clinical triad of SS. The diagnosis of MS was excluded, and glatiramer acetate therapy was discontinued. The patient's neurological state improved only after the use of a combination of corticosteroids, intravenous immunoglobulins, and azathioprine. CONCLUSIONS: The coincidence of SS signs and symptoms with treatment for MS, first with interferon beta-1a and then with glatiramer acetate, suggests that these drugs may influence the course of SS. This case report indicates that treatment with glatiramer acetate may modulate or even exacerbate the course of SS.

Single Diastereomers of the Clinical Anticancer ProTide Agents NUC-1031 and NUC-3373 Preferentially Target Cancer Stem Cells In Vitro.

A 3'-protected route toward the synthesis of the diastereomers of clinically active ProTides, NUC-1031 and NUC-3373, is described. The in vitro cytotoxic activities of the individual diastereomers were found to be similar to their diastereomeric mixtures. In the KG1a cell line, NUC-1031 and NUC-3373 have preferential cytotoxic effects on leukemic stem cells (LSCs). These effects were not diastereomer-specific and were not observed with the parental nucleoside analogues gemcitabine and FUDR, respectively. In addition, NUC-1031 preferentially targeted LSCs in primary AML samples and cancer stem cells in the prostate cancer cell line, LNCaP. Although the mechanism for this remains incompletely resolved, NUC-1031-treated cells showed increased levels of triphosphate in both LSC and bulk tumor fractions. As ProTides are not dependent on nucleoside transporters, it seems possible that the LSC targeting observed with ProTides may be caused, at least in part, by preferential accumulation of metabolized nucleos(t)ide analogues.

Does the operator's sex matter? An analysis based on the national interventional cardiology registry.

BACKGROUND: A small number of female cardiologists work in the field of interventional cardiology. Such disparity is observed in most European countries. AIMS: We present the first national report on the practice patterns and outcomes regarding percutaneous coronary interventions (PCIs) performed by female operators (FOs) in Poland. METHODS: Data were collected from the National Registry of Invasive Cardiology Procedures (Ogólnopolski Rejestr Procedur Kardiologii Inwazyjnej [ORPKI]) between January 2014 and December 2017. RESULTS: A total of 31 FOs (4.1%) performed 12 935 PCIs (2.8%). The median (interquartile range [IQR]) number of PCIs performed by FOs per year was 75 (43-154), whereas that by male operators was 139 (67-216; P <0.01). Patients handled by FOs were characterized by a lower prevalence of cardiovascular risk factors and previous coronary artery interventions. Acute coronary syndrome was the main indication for treatment (74.66%). Compared with male operators, FOs handled significantly more patients with single­vessel disease (87.02% vs 84.72%; P <0.001). They used smaller contrast doses during PCIs (median [IQR], 170.36 [77.54] cm3 vs 173.48 [77.54] cm3; P <0.001) yet higher doses of radiation exposure (median [IQR], 843 [472-1409] mGy vs 815 [458-1390] mGy; P = 0.01). There was no difference in clinical outcomes (a composite of all­cause death, bleeding at the puncture site, or coronary artery perforation) associated with the operator's sex. CONCLUSIONS: Women represent a minority of operators in interventional cardiology and are responsible for a low percentage of PCIs. Nonetheless, the practice patterns and outcomes of PCIs performed by FOs are similar to those of male operators.

Knowledge on the guideline-recommended use of antiplatelet and anticoagulant therapy during dental extractions: a contemporary survey among Polish dentists.

BACKGROUND: The number of dental patients requiring periodic or lifelong antiplatelet or anticoagulanttherapy is constantly growing. AIMS: We aimed to determine the level of knowledge on antiplatelet and anticoagulant therapy among Polish dentists. METHODS: self­designed online questionnaire was distributed among dentists to evaluate their knowledge on the use of antiplatelet and anticoagulant drugs in clinical dental practice. RESULTS: The study included 352 dentists. Patients requiring vitamin K antagonists were referred for a cardiac consultation by 64.52%, 57.29%, and 58.55% of dentists with <5, 5-15, and >15 years of experience,respectively (P = 0.003). A similar trend was observed for non-vitamin K antagonist oral anticoagulants among nonsurgical dentists. However, an equal percentage of surgical dentists (39.7%) performedextraction with and without consultation, and they were more likely to perform extraction withoutconsultation than nonsurgical dentists (39.7% vs 27.8%; P = 0.01). Most surgical and nonsurgical dentistspreferred to consult a cardiologist about dual antiplatelet therapy before an invasive procedure (56.9%and 73.81%, respectively; P = 0.03). Extractions in patients on aspirin were accepted by 75.81%, 70.83%, and 49.34% of dentists with <5, 5-15, and >15 years of experience, respectively (P = 0.004), and by 79.31%of surgical and 57.14% of nonsurgical dentists (P = 0.003). CONCLUSIONS: Knowledge on antiplatelet and anticoagulant therapy in patients undergoing dental procedures is unsatisfactory among Polish dentists. Both therapies were discontinued before extractionsmore frequently than recommended in the guidelines, while extractions in patients on aspirin were common.

Cerebral palsy and obstetric-neonatological interventions.

Cerebral palsy is a disease that puts a great mental burden on caregivers and generates very high social costs. Children with CP require many years of rehabilitation and medical care. The etiology of the disease is undoubtedly multifactorial, and the pathogenesis is associated with focal damage to the central nervous system. One can find descriptions of well-documented interventions in the literature that reduce the risk of CP in certain groups of pregnant and neonatal patients, and interventions that have a potentially protective effect. In this review, we have analyzed the available literature in terms of prenatal and postnatal interventions that may have an impact on reducing the incidence of this condition in children.

Symmetrical Diamidates as a Class of Phosphate Prodrugs to Deliver the 5'-Monophosphate Forms of Anticancer Nucleoside Analogues.

The application of phosphorodiamidate technology to pyrimidine and purine nucleosides with anticancer activity to potentially overcome the resistance mechanisms associated with parent nucleosides is reported. Sixteen symmetrical phosphorodiamidates were prepared from the natural amino acids l-alanine and glycine. All the compounds were evaluated for their cytotoxic activity against a wide panel of solid and leukaemic tumour cell lines. In addition, a carboxypeptidase Y assay was performed on a representative phosphorodiamidate in order to reveal the putative bioactivation pathway for the reported phosphorodiamidate-type prodrugs.

Phosphoramidates and phosphonamidates (ProTides) with antiviral activity.

Following the first report on the nucleoside phosphoramidate (ProTide) prodrug approach in 1990 by Chris McGuigan, the extensive investigation of ProTide technology has begun in many laboratories. Designed with aim to overcome limitations and the key resistance mechanisms associated with nucleoside analogues used in the clinic (poor cellular uptake, poor conversion to the 5'-monophosphate form), the ProTide approach has been successfully applied to a vast number of nucleoside analogues with antiviral and anticancer activity. ProTides consist of a 5'-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which once in the cell is enzymatically metabolized to deliver free 5'-monophosphate, which is further transformed to the active 5'-triphosphate form of the nucleoside analogue. In this review, the seminal contribution of Chris McGuigan's research to this field is presented. His technology proved to be extremely successful in drug discovery and has led to two Food and Drug Administration-approved antiviral agents.

Synthesis and biological evaluation of 6-substituted-5-fluorouridine ProTides.

A new family of thirteen phosphoramidate prodrugs (ProTides) of different 6-substituted-5-fluorouridine nucleoside analogues were synthesized and evaluated as potential anticancer agents. In addition, antiviral activity against Chikungunya (CHIKV) virus was evaluated using a cytopathic effect inhibition assay. Although a carboxypeptidase Y assay supported a putative mechanism of activation of ProTides built on 5-fluorouridine with such C6-modifications, the Hint docking studies revealed a compromised substrate-activity for the Hint phosphoramidase-type enzyme that is likely responsible for phosphoramidate bioactivation through P-N bond cleavage and free nucleoside 5'-monophosphate delivery. Our observations may support and explain to some extent the poor in vitro biological activity generally demonstrated by the series of 6-substituted-5-fluorouridine phosphoramidates (ProTides) and will be of guidance for the design of novel phosphoramidate prodrugs.

Therapeutic use of fluorinated nucleosides - progress in patents.

Fluorinated nucleosides constitute a large class of chemotherapeutics approved for clinical use. The pharmacokinetic and pharmacodynamic properties of a drug can be affected, as a consequence of modulation of electronic, lipophilic and steric parameters, by the introduction of fluorine into the structure of drug-like molecule. Herein, we focus on fluorinated-nucleoside analogs, their therapeutic use and applications based on the patent literature from 2014 to 2018. We briefly discuss the clinical properties of anticancer and antiviral fluorine-containing nucleos(t)ides US FDA-approved or in development, and highlight their resistance mechanisms and limitations in the clinic. We emphasize patent inventions related to improved synthetic methods toward selected nucleos(t)ide analogs including the phosphoramidate sofosbuvir and 18F-labeled nucleosides FLT and FMAU, used as a 18F-PET tracers.

Fluorinated nucleosides as an important class of anticancer and antiviral agents.

Fluorine-containing nucleoside analogs (NAs) represent a significant class of the US FDA-approved chemotherapeutics widely used in the clinic. The incorporation of fluorine into drug-like agents modulates lipophilic, electronic and steric parameters, thus influencing pharmacodynamic and pharmacokinetic properties of drugs. Fluorine can block oxidative metabolism of drugs and the formation of undesired metabolites by changing H-bonding interactions. In this review, we focus our attention on chemical fluorination reagents and methods used in the NAs field, including positron emission tomography radiochemistry. We briefly discuss both the cellular biology and clinical properties of FDA-approved and fluorine-containing nucleoside/nucleotide analogs in development as well as common resistance mechanisms associated with their use. Finally, we emphasize pronucleotide strategies used to improve therapeutic outcome of NAs in the clinic.

Synthetic Approaches for the Preparation of Phosphoramidate Prodrugs of 2'-Deoxypseudoisocytidine.

A synthetic procedure for the preparation of phosphoramidate prodrugs of C-nucleosides is reported. Different phosphorochloridates were reacted with 3'-O-protected N-acetyl-2'-deoxypseudoisocytidine or 3'-O-protected 2'-deoxypseudoisocytidine, followed by acidic hydrolysis of the protecting group. In the presence of the N-acetyl moiety, the enolisable keto group of the nucleobase was able to react (like the 5'-OH) with the phosphorochloridates to give bisphosphorylated derivatives. Epimerisation (ß to α) occurred if the amino group of the nucleobase was unprotected. These side reactions demonstrate the peculiar behaviour of C-nucleosides compared to their nucleoside analogues. It was demonstrated that the first enzymatic activation step for this new class of prodrugs can be mediated by carboxypeptidase and that it follows the same pathway and rate reported for ProTides of more conventional nucleoside analogues. These new phosphoramidate derivatives deserve further investigation for their therapeutic potential as anti-cancer agents.