Pharmacological Parameters Research Articles

Sources of Antifungal Drugs

Due to their eukaryotic heritage, the differences between a fungal pathogen's molecular makeup and its human host are small. Therefore, the discovery and subsequent development of novel antifungal drugs are extremely challenging. Nevertheless, since the 1940s, researchers have successfully uncovered potent candidates from natural or synthetic sources. Analogs and novel formulations of these drugs enhanced the pharmacological parameters and improved overall drug efficiency. These compounds ultimately became the founding members of novel drug classes and were successfully applied in clinical settings, offering valuable and efficient treatment of mycosis for decades. Currently, only five different antifungal drug classes exist, all characterized by a unique mode of action; these are polyenes, pyrimidine analogs, azoles, allylamines, and echinocandins. The latter, being the latest addition to the antifungal armamentarium, was introduced over two decades ago. As a result of this limited arsenal, antifungal resistance development has exponentially increased and, with it, a growing healthcare crisis. In this review, we discuss the original sources of antifungal compounds, either natural or synthetic. Additionally, we summarize the existing drug classes, potential novel candidates in the clinical pipeline, and emerging non-traditional treatment options.

To Explore the Key Active Compounds and Therapeutic Mechanism of Guizhi Gancao Decoction in Coronary Heart Disease by Network Pharmacology and Molecular Docking.

Coronary heart disease (CHD) is the leading cause of death from cardiovascular disease and has become an important public health problem worldwide. Guizhi Gancao Decoction (GGD) has been shown to be used in the treatment of CHD with good efficacy, but its specific therapeutic mechanism and active ingredients have not been fully clarified. This study aims to identify the active compounds and key targets of GGD in the treatment of CHD, explore the therapeutic mechanism of GGD, and provide candidate compounds for anti-CHD drug development. The main compounds of GGD were determined by UPLC-MS/MS analysis and screened by SwissADME. The corresponding targets of GGD compounds were obtained from SwissTargetPrediction, and the targets of CHD were obtained from the HERB and GeneCards databases. The STRING 11.5 database was used to analyze the PPI (Protein-Protein Interactions) network of potential therapeutic targets of GGD compounds. Cytoscape 3.7.2 was used to construct target-related networks and find core targets. The GEO database was used to validate the differential expression of core targets. The PANTHER Classification System was used to functionally classify potential therapeutic targets for GGD. The GO biological process analysis and KEGG pathway analysis of targets were completed by DAVID 6.8 database. AutoDockTools 1.5.6 and PyMol 2.5.2 were used to perform molecular docking of core targets with the active GGD compounds. 7 active GGD compounds were obtained based on UPLC-MS/MS and pharmacological parameter evaluation, which corresponded to 131 CHD-related targets. Among them, EGFR, MAPK3, RELA, CCND1, ESR1, PTGS2, NR3C1, CYP3A4, MMP9, and PTPN11 were considered core targets. According to the targets related to CHD, glycyrrhetinic acid, liquiritigenin, and schisandrin are considered key active ingredients. GO biological process and KEGG analysis indicated that the potential targets of GGD in the treatment of CHD involve a variety of biological processes and therapeutic mechanisms. Molecular docking results showed that both the core targets and the corresponding compounds had the good binding ability. This study contributes to a more comprehensive understanding of the therapeutic mechanism and active ingredients of GGD for CHD and provides candidate compounds for drug development of CHD.

Allosteric binding cooperativity in a kinetic context

Allosteric modulators are of prime interest in drug discovery. These drugs regulate the binding and function of endogenous ligands, with some advantages over orthosteric ligands. A typical pharmacological parameter in allosteric modulation is binding cooperativity. This property can yield unexpected but illuminating results when decomposed into its kinetic parameters. Using two reference models (the allosteric ternary complex receptor model and a heterodimer receptor model), a relationship has been derived for the cooperativity rate constant parameters. This relationship allows many combinations of the cooperativity kinetic parameters for a single binding cooperativity value obtained under equilibrium conditions. This assessment may help understand striking experimental results involving allosteric modulation and suggest further investigations in the field.

Polypharmacy-related polypathology in the elderly: A case study at Ibn Sina Hospital, Morocco

Purpose: To determine the polypathological and therapeutic profiles of a population of elderly subjects at the Ibn Sina Hospital, Rabat, Morocco. 
 Methods: This was a prospective cross-sectional observational study on a population made up of 356 patients aged ≥ 65 years. Data were collected from different departments during the study period, regarding age, sex, educational level, socio-cultural and economic status, self-care ability, polypathologies, polymedication, effectiveness of treatments, adverse effects, and knowledge of the concept of generic medication. The results, which are presented in percentages and simple averages, were processed with Excel 2016 software. 
 Results: Patients aged 66 - 75 years comprised 60.4 % of the studied population. The most common pathologies were diabetes, asthma, and cardiovascular disease. A total of 237 patients (66.6 %) took < 6 drugs, while 119 patients (33.4 %) were on polypharmacy, i.e., > 6 drugs. The elderly were more vulnerable to polypathology and polypharmacy due to age-related reduction in physiological functions and their impact on pharmacological parameters. Polypathology led to polypharmacy which increased the risk of side effects and problems with adherence to medications. 
 Conclusion: This study provides information on the pathological profiles of a population of elderly subjects in a Moroccan hospital, and details of the therapeutic strategies used in managing these patients.

Spectroscopic characterization of different protonation/deprotonation states of Barbaloin in aqueous solution

Barbaloin (10–glucopyranosyl–1,8–dihydroxy–3–(hydroxymethyl)–9(10H)–anthraquinone: aloin A), present in Aloe species, is widely used in food, cosmetic and pharmaceutical industries. Here we characterize its optical absorption and emission spectra in aqueous solution at different pH values. Through pH titration, using both absorption and fluorescence spectroscopy, two pKa values for Barbaloin were determined: pKa1=9.6±0.6 and pKa2=12.6±0.8. These acidity constants were found to be higher than those found for Emodin, a similar molecule which lacks the sugar moiety present in Barbaloin. Performing quantum mechanical calculations for non-ionized, singly, doubly, and triply deprotonated forms of Barbaloin in vacuum and in water, we assigned the positions of the site for the first and third deprotonation in the anthraquinone group, and the second deprotonation in the glucose group. The instability of Barbaloin in high pH solutions is discussed here, and the optical absorption and fluorescence spectra due to products resulted from Barbaloin degradation at high pH is well separated from the Barbaloin original spectra. Biological fluids have specific pH values to maintain homeostasis, hence determining the pKa of Barbaloin is important to evaluate the mechanism of action of this drug in different parts of an organism as well as to predict pharmacological relevant parameters, such as absorption, distribution, metabolism, and excretion.

The toxicological effects of Eryngium foetidum extracts on zebrafish embryos and larvae depend on the type of extract, dose, and exposure time.

Eryngium foetidum is a herbaceous plant found in tropical and subtropical regions. In vivo pharmacological parameters show that leaf extracts of this plant have antioxidant, anti-inflammatory, antidiabetic, and antimicrobial activities due to their bioactive compounds such as flavonoids and phenols. Despite the evidence for several bioactivities of E. foetidum, information on its safety and tolerability is limited. The objective of this study was to assess the effect and concentration of different extracts of E. foetidum on the development of zebrafish (Danio rerio) embryos. To study the impact of aqueous (AE), ethanolic (EE), and methanolic (ME) extracts, the embryos were exposed to 0.625, 1.25, 2.5, 5, and 10mgmL-1 for up to 120-h postfertilization to assess embryonic developmental toxicity and then to 0.039, 0.078, 0.156, 0.312, and 0.625mgmL-1 to assess the antioxidant responses of the enzymes superoxide dismutase catalase, glutathione S-transferase (GST), and cell apoptosis. The results showed that, depending on the extraction solvent, concentration used, and exposure time, E. foetidum extracts caused mortality, altered the hatching time, and promoted changes in enzymatic activities. Delays in development and increased GST activity were found in all treatments. Apoptosis was not observed in any of the treatments. In conclusion, AE, EE, and ME concentrations above 0.625mgmL-1 can cause adverse effects on the early stages of zebrafish development.

Triterpenoid pyrazines and pyridines – Synthesis, cytotoxicity, mechanism of action, preparation of prodrugs

A set of fifteen triterpenoid pyrazines and pyridines was prepared from parent triterpenoid 3-oxoderivatives (betulonic acid, dihydrobetulonic acid, oleanonic acid, moronic acid, ursonic acid, heterobetulonic acid, and allobetulone). Cytotoxicity of all compounds was tested in eight cancer and two non-cancer cell lines. Evaluation of the structure-activity relationships revealed that the triterpenoid core determined whether the final molecule is active or not, while the heterocycle is able to increase the activity and modulate the specificity. Five compounds (1b, 1c, 2b, 2c, and 8) were found to be preferentially and highly cytotoxic (IC50 ≈ 1 μM) against leukemic cancer cell lines (CCRF-CEM, K562, CEM-DNR, or K562-TAX). Surprisingly, compounds 1c, 2b, and 2c are 10-fold more active in multidrug-resistant leukemia cells (CEM-DNR and K562-TAX) than in their non-resistant analogs (CCRF-CEM and K562). Pharmacological parameters were measured for the most promising candidates and two types of prodrugs were synthesized: 1) Sugar-containing conjugates, most of which had improved cell penetration and retained high cytotoxicity in the CCRF-CEM cell line, unfortunately, they lost the selectivity against resistant cells. 2) Medoxomil derivatives, among which compounds 26–28 gained activities of IC50 0.026–0.043 μM against K562 cells. Compounds 1b, 8, 21, 22, 23, and 24 were selected for the evaluation of the mechanism of action based on their highest cytotoxicity against CCRF–CEM cell line. Several experiments showed that the majority of them cause apoptosis via the mitochondrial pathway. Compounds 1b, 8, and 21 inhibit growth and disintegrate spheroid cultures of HCT116 and HeLa cells, which would be important for the treatment of solid tumors. In summary, compounds 1b, 1c, 2b, 2c, 24, and 26–28 are highly and selectively cytotoxic against cancer cell lines and were selected for future in vivo tests and further development of anticancer drugs.

245.9: Influence of Tacrolimus CYP3A5 Polymorphisms on the Doselevel Response After Pediatric Kidney Transplantation

Background: Tacrolimus exhibits wide inter and intra-patient variability. CYP3A5 tacrolimus polymorphisms predict its metabolization. We aim to identify the influence of polymorphisms on the pharmacological parameters. The present report is part of the exploratory data analysis of a pediatric trial that used the initial tacrolimus dose according to the CYP3A5 genotype in kidney transplant recipients. Methods: We performed an exploratory data analysis of pharmacological parameters from a single-center, non-randomized, open-label clinical trial in children from 0-to 18 years of age who received a kidney transplant at the Hospital Infantil de México, Federico Gómez from January 2013 to December 2018. All children were genotyped before transplantation and assigned to one of two groups: the Genotype-guided group, which initial dose was according to the CYP3A5 polymorphisms and the Conventional-dose group (see abstract AID-1780), with further dose adjustments on the decision of the clinicians. We followed them for six weeks and recorded tacrolimus dose received, trough level achieved, deltas of dose and trough levels between time points (weekly). Results: We included 81 subjects; 40 received the genotype-guided dose, the mean age at transplantation was 13.3 y/o, 51.8% were female. After six weeks of transplantation, linear regressions showed no linear associations between tacrolimus dose and levels in the genotype-guided dose group (r2=0.0003, p=0.78) or the conventional-dose group (r2=0.0008, p=67). However, there were linear associations between the delta-dose and delta-levels in the genotype-guided dose group (r2=0.138, p=<0.0001) and conventional-dose group (r2=0.081, p=<0.0001). The subgroup analysis by genotype showed that AG1*3 polymorphism had a linear association between the tacrolimus delta-dose and delta-level (r2=0.168, p=<0.001). Furthermore, It reached statistical significance in the tacrolimus dose vs level analysis (r2=0.0308, p= 0.02). The GG3*3 polymorphism showed an association only in the delta-dose vs delta-level analysis (r2=0.057, p=<0.001), while the AA1*1 genotype did not show any linear associations between tacrolimus dose vs trough level or deltas (r2=0.006, p=0.64 and r2=0.108, p=0.08 respectively) (Figure). Conclusion: The tacrolimus delta-dose and delta-level across the different polymorphisms translate the clinician’s decisions. The trough levels’ response to dose adjustments might be guided by the CYP3A5 genotypes, specifically the AG1*3. Further studies are needed to estimate more accurate associations.

Sex Differences in Clinical Parameters, Pharmacological and Health-Resource Utilization in a Population With Hypertension Without a Diagnosis of COVID-19.

Objectives: Determine the changes in clinical, pharmacological and healthcare resource use parameters, between the 6 months prior to the lockdown and the 6 months following its end, in a population with hypertension who did not have a diagnosis of COVID-19. Methods: Real world data observational study of 245,979 persons aged >16 years with hypertension in Aragon (Spain). Clinical (systolic-diastolic blood pressure, estimated glomerular filtration rate (eGFR), blood creatinine, cholesterol, triglycerides and anthropometric measures); pharmacological (diuretics, calcium channel antagonists, and ACE inhibitors); and utilization of healthcare resources were considered. We performed the Student’s T-test for matched samples (quantitative) and the Chi-squared test (qualitative) to analyze differences between periods. Results: SBP, DBP, parameters of renal function and triglycerides displayed a significant, albeit clinically irrelevant, worsening in women. In men only DBP and eGFR showed a worsening, although to a lesser extent than in women. Certain antihypertensive drugs and health-resource utilization remained below pre-pandemic levels across the 6 months post-lockdown. Conclusion: Changes in lifestyles, along with difficulties in access to routine care has not substantially compromised the health and quality of life of patients with hypertension.

Rottlerin promotes anti-metastatic events by ameliorating pharmacological parameters of paclitaxel: An in-vivo investigation in the orthotopic mouse model of breast cancer

Despite substantial breakthroughs in cancer research, there is hardly any specific therapy available to date that can alleviate triple-negative breast cancer (TNBC). Paclitaxel is the first-line chemotherapy option, but its treatment is often associated with early discontinuation of therapy due to the development of resistance and/or precipitation of severe side effects. In the quest to establish a suitable combination therapy with a low dose of paclitaxel, we explored rottlerin (a pure and characterized phytoconstituent from Mallotus philippensis) because of its multifaceted pharmacological actions against cancer. The study was performed to assess the therapeutic effects of rottlerin (5–20 mg/kg) with a low dose of paclitaxel (5 mg/kg) using a highly aggressive mouse mammary carcinoma model. Rottlerin augmented the paclitaxel effect by reducing tumor burden as well as metastatic lung nodules formation. Rottlerin in combination with paclitaxel remarkably altered the expression of vital epithelial-mesenchymal transition (EMT) markers such as E-cadherin, Snail 1, & Vimentin and thus improved the anti-metastatic efficacy of paclitaxel. Significant attenuation of anti-apoptotic protein (Bcl-2) along with amplification of pro-apoptotic (cleaved PARP) marker confers that rottlerin could ameliorate the pro-apoptotic potential of paclitaxel. In this study, a rational combination of rottlerin and paclitaxel treatment curtailed CYP2J2 expression and epoxyeicosatrienoic acids (EETs) levels, responsible for restrain tumor growth and metastasis. Additionally, rottlerin lessened paclitaxel treatment-mediated hematological alterations and prevented paclitaxel treatment-linked key serum biochemical changes related to organ toxicities. These rottlerin treatment-mediated protective changes are closely associated with the lower paclitaxel accumulation in the corresponding tissues. Rottlerin caused significant pharmacokinetic interaction with paclitaxel to boost the plasma level of paclitaxel in a typical mouse model and possibly helpful towards the use of a low dose of paclitaxel in combination. Overall, it can be stated that rottlerin has significant potential to augment the anti-metastatic efficacy of paclitaxel via impeding EMT activation along with attenuating its treatment-associated toxicological alterations. Hence, rottlerin has significant potential to explore further as a suitable neoadjuvant therapy with paclitaxel against TNBC.

Effect of Mentone® on depression- and anxiety-like profiles and regional brain neurochemistry in the adolescent Wistar Kyoto rat, a putative model of endogenous depression

Objectives: Antidepressants, when prescribed to treat adolescent depression tend to induce adverse effects, including suicidal tendencies. This is because the adolescent brain circuitry is still maturing and is therefore extremely vulnerable. As such, the search is on for compounds for use in complementary/alternative medicine. Polyherbal formulations are widely used as therapeutic alternatives for the treatment of depression. Such formulations and plant extracts are being studied in adult rodent models using standard pharmacological parameters, but not much emphasis has been given to testing the same in adolescents and endogenous animal models of depression. Therefore, the present study was focused on testing out the effect of the polyherbal formulation Mentone® on depression- and anxiety-like profiles and brain neurochemistry in the adolescent Wistar Kyoto rat (WKY), a putative model of endogenous and treatment-resistant depression (TRD). Materials and Methods: Mentone®, a polyherbal formulation comprising of four different plant species: Centella asiatica (Brahmi), Evolvulus alsinoides (Shankapushpi), Tinospora cordifolia (Guduchi), and Glycyrrhiza glabra (Yashtimadhu) was tested at two (18 and 36 mg/kg body weight) doses from the post-natal day (pnd) 25 to pnd 42 using standard neurobehavioral paradigms. Vehicular controls were intubated with saline and positive controls with 10 mg/kg body weight of conventional antidepressant, Fluoxetine. From pnd 35 onwards, animals were tested on a battery of tests, including sucrose preference, novel open field, elevated plus maze, and forced swim or Porsolt’s learned helplessness test. On pnd 42, animals were sacrificed and brain regional tissues such as the Prefrontal cortex (PFC), Striatum (Str), Nucleus Accumbens (NAc), and Hippocampus were microdissected out and subjected to reverse phase HPLC for the separation and quantification of monoamines: Norepinephrine (NE), dopamine (DA), serotonin (5-HT) and their metabolites, 3,4-Dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) in reference to external standards. Results: Mentone® reversed anhedonia by increasing sucrose consumption in Mentone®-treated as compared to Fluoxetine-treated groups. However, there was no effect on anxiety-related parameters in the novel open field or elevated plus-maze. Mentone® exhibited significant anti-depressant-like effects as indicated by its ability to reduce swim stress-induced immobility in Porsolt’s behavioural despair test with a concomitant increase in climbing or struggling behaviour, signifying reversal of depressive-like symptomatology. HPLC-based separation and quantification of brain regional levels of monoamines and their metabolites revealed increased DA levels in NAc and Str in treated groups with decreased levels of metabolite DOPAC in Mentone®-treated groups indicating increased DA tone. Significantly reduced 5-HT metabolite 5-HIAA levels in both PFC and Str is indicative of increased 5-HT tone in both Mentone®- and Fluoxetine-treated groups. NE was variably affected. Conclusion: While no anxiolytic effects and differential neurochemical effects were observed in brain regional areas in relation to Mentone® and Fluoxetine treatment, anhedonia and forced swim test, which are gold-standard tests for assessing depressive-like profiles indicated an effect of Mentone® that was on par with Fluoxetine. Thus, studies on such Ayurvedic formulations would enable a teasing out or differentiation between anxiolytic-like and depressive-like symptomatology and could constitute a source that holds promise in the development of complementary/alternative therapies for the treatment of depression in general and TRD in particular.

PET imaging to assess fibroblast activation protein inhibitor biodistribution: A training program adapted to pharmacology education

In the process of pharmacology education, practical teaching is an important complement to theoretical teaching. These activities include the use of experimental animals to obtain certain pharmacological parameters or to help students understand certain classical concepts. However, the growing interest in laboratory animal welfare, the rapid development of pharmacology research and the challenges of cultivating innovative pharmacy talent create a need for innovative and flexible in vitro experiments for teaching purposes. Here, we report the application of positron emission tomography (PET) imaging of 18F‐labeled fibroblast activation protein inhibitor (18F‐FAPi) to practical pharmacology teaching, enabling dynamic visualization of the distribution and excretion process of FAPi in mice. Students can quantitatively analyze the distribution of FAPi in various tissues and organs without sacrificing the mice. Furthermore, the newly implemented method resulted in highly reproducible results and was generally appreciated by the students. Additionally, the application of PET imaging in pharmacokinetic teaching can not only greatly reduce the use of experimental animals but also need not sacrificing animals. Of note is that dynamic scanning data from this project can be used for online practical teaching during COVID‐19 pandemic.

Impact of Inflammation on Intra-individual Variation in Trough Voriconazole Concentration in Patients with Hematological Malignancies

The pharmacokinetics of voriconazole shows large intra-individual and inter-individual variability and is affected by various factors. Recently, inflammation has been focused as a significant factor affecting the variability. This study aimed to compare the influence of C-reactive protein (CRP) and other clinical laboratory parameters on intra-individual variability in trough voriconazole concentration and examine the impact of inflammation in patients with hematological malignancies. We conducted a retrospective, single-center, observational cohort study. Forty-two patients with hematological malignancy who received oral voriconazole for prophylaxis against deep mycosis and underwent multiple measurements of trough plasma voriconazole concentration were recruited. Quantitative changes in pharmacological and clinical laboratory parameters (Δ) were calculated as the difference between the current and preceding measurements. Voriconazole concentration/maintenance dose per weight (C/D) was found to correlate positively with CRP level (n = 202, rs = 0.314, p < 0.001). Furthermore, ΔC/D correlated positively with ΔCRP level (n = 160, rs = 0.442, p < 0.001), and ΔCRP showed the highest correlation coefficient among the laboratory parameters. Univariate and multivariate analyses identified ΔCRP (p < 0.001) and Δgamma-glutamyl transpeptidase (γGTP) (p = 0.019) as independent factors associated with ΔC/D. Partial R2 were 0.315 for ΔCRP and 0.024 for ΔγGTP, suggesting markedly greater contribution of ΔCRP to ΔC/D. In conclusion, since clinical laboratory parameters other than CRP had little influence on trough plasma voriconazole concentration, therapeutic drug monitoring and dose adjustment considering fluctuation in CRP level would be important for proper use of voriconazole in patients with hematological malignancies.

Experimental Study of the Efficacy and Safety of a New PEG-Based Laxative

Bowel-cleansing PEG-based agents, including Moviprep®, are commonly used to prepare the large intestine for diagnostic examinations. PLNV-next is a newly developed fixed combination medicinal product with a composition similar to that of Moviprep®.The aim of the study was to estimate the pharmacological efficacy and toxicity of PLNV-next.Materials and methods: The study evaluated pharmacological efficacy of four formulations of PLNV-next in comparison with Moviprep® after a single administration in a therapeutic dose to outbred rats. The evaluation was carried out based on the laxative effect of the medicinal products. The authors recorded diarrhoea onset latency and the number of defecation boluses and diarrhoea spots produced during the 6-hour observation period. Toxicity of PLNV-next was studied in the formulation containing maximum amounts of the ingredients according to the patent. In the single-dose toxicity study, PLNV-next was administered intragastrically to rats at doses of 4.2 g/kg (maximum human therapeutic dose, MHTD), 21 g/kg (5 MHTD), and 42 g/kg (10 MHTD) and to ferrets at doses of 4.2 g/kg (MHTD) and 21 g/kg (5 MHTD). In the repeated-dose toxicity study, PLNV-next was administered for 14 days at 4.2 g/kg (rats and ferrets), 21 g/kg (5 MHTD, rats), and 12.6 g/kg (3 MHTD, ferrets). Additionally, the repeated-dose toxicity study evaluated safety pharmacology parameters for the cardio-vascular, respiratory and central nervous systems.Results: All PLNV-next formulations tested exerted a laxative effect equivalent to that of Moviprep®. No clinical signs of toxicity were observed in rats, with the exception of the laxative effect. Ferrets demonstrated decreased behavioral activity and diarrhoea. Nausea or emesis were noted in 75–90% of the ferrets receiving the doses exceeding the MHTD. A single administration of PLNV-next affected blood sodium concentrations: a slight increase was noted in the 5 MHTD and 10 MHTD groups of rats and in the 5 MHTD group of ferrets. The repeated-dose toxicity study in rats revealed a slight increase in sodium levels with both test doses. After a single administration of 5 MHTD to ferrets, the authors observed a decrease in potassium levels. All the changes were mild and within physiological ranges. PLNV-next toxic effects observed in the rat and ferret studies were similar to those reported in rat and dog toxicity studies of Moviprep®. Conclusion: PLNV-next exerts a marked laxative effect and has a favourable safety profile.

Inhibition of α-glucosidase by Cyclocarya paliurus based on HPLC fingerprinting integrated with molecular docking and molecular dynamics.

Cyclocarya paliurus (CP) extracts have been shown to lower sugar and lipid levels in blood, but the material basis is not clear. We analyzed CP aqueous extracts using high-performance liquid chromatography "fingerprinting", checked their pharmacological parameters using virtual screening, and undertook molecular docking and molecular dynamics simulations. Also, the inhibitory effects of CP components upon α-glucosidase in vitro were evaluated. Fingerprinting and virtual screening showed that the aqueous extract of CP contained the active components protocatechuic acid, chlorogenic acid, caffeic acid and rutin, which were safe and had no side effects in vivo. Molecular docking and molecular dynamics simulations showed that chlorogenic acid and rutin might have a potent inhibitory effect on α-glucosidase. An enzyme-activity assay in vitro showed that the half-maximal inhibitory values of chlorogenic acid and rutin were 398.9 and 351.8μg/ml, respectively. Chlorogenic acid and rutin had an inhibitory effect on α-glucosidase. Cyclocarya paliurus could be developed as a natural α-glucosidase inhibitor.

C57 DUAL ANTIPLATELET THERAPY DID NOT PREDICT ALL–CAUSE BLEEDING AT LONG–TERM FOLLOW–UP AFTER ACS: A SUBANALYSIS FROM THE APULIA PONTE ACS STUDY

Abstract Background Dual antiplatelet therapy (DAPT) has important implications for clinical outcomes in coronary disease. Nevertheless, the risk for bleeding often impact on the long–term administration of DAPT. The aim of this study was to evaluate the determinants of bleeding risk after ACS. Methods This was a subanalysis of the PONTE ACS study. The PONTE ACS study is a prospective, longitudinal, cohort study which enrolled patients who were discharged from HUB centres of ASL BARI after coronary revascularization and/or ACS. They underwent clinical evaluation at 30 days, 3, 6 and 1 year–follow–up. The data were collected after including the data in the electronic medical record of the PONTE ACS study. Anthropometric, clinical and pharmacological parameters, instrumental and laboratory examinations were included. Data were computed in order to evaluate the major determinants of all–cause bleeding at one–year follow–up. Results We finally enrolled 2476 patients (77.4% male, mean age: 67.2±12.0 years). Pharmacological treatments were optimized during the follow–up visits. According to anti–thrombotic therapies, 92.1% of patients persisted on DAPT at one–year follow–up. The number of patients on DAPT+anticoagulant were: 4.4%. All–cause bleeding occurred in 2.2% of patients. Anthropometric characteristics (height [β: –0.04594 ± 0.01610, p = 0.0044] and weight [β: –0.03043 ± 0.01035, p = 0.033]), male gender [β: –0.7008 ± 0.2818, p = 0.0129], and age [β: 0.02535 ± 0.01219, p = 0.0376] were the major determinants of all–cause bleeding at univariate regression analysis but they were not confirmed at multivariate regression analysis (p=ns). Kaplan Meier curve points out the impact of age on all–cause bleeding (Figure 1). Nor DAPT or triple therapy remained associated with all–cause bleeding at one year follow–up. Conclusions Long–term DAPT is not a predictor of all–cause bleeding in patients who suffered ACS and/or coronary revascularization.

C56 THE IMPACT OF STATIN THERAPY ON THE PROGNOSIS OF PATIENTS DISCHARGED AFTER ACUTE CORONARY SYNDROME: A SUBANALYSIS OF THE APULIA PONTE ACS STUDY

Abstract Background The administration of statin therapy in patients who suffered from acute coronary syndrome (ACS) is fundamental in order to avoid recurrences and adverse cardiovascular events. The long–term adherence and persistence on statin therapy is challenging. The aim of this study was to evaluate the prognostic impact of a dedicated follow–up outpatient program for patients who were discharged with the diagnosis of ACS on adherence and persistence on statin therapy. Methods This was a subanalysis of the PONTE ACS study. The PONTE ACS study is a prospective, longitudinal, cohort study which enrolled patients who were discharged from HUB centres of ASL BARI after coronary revascularization and/or ACS. They underwent clinical evaluation at 30 days, 3, 6 and 1 year–follow–up. The data were collected after including the data in the electronic medical record of the PONTE ACS study. Anthropometric, clinical and pharmacological parameters, instrumental and laboratory examinations were included. The following endpoints were considered: all cause death, ACS recurrence/cardiac ischemia/angina, restenosis/intrastent thrombosis, stroke/transient ischemic attack (TIA), heart failure, all–cause bleeding. Results We enrolled 2476 patients (mean age: 67.2±12.0 years). At 1–year follow–up optimal medical therapy was reached in most of patients: 84.1% were on beta–blockers, 63.1% on ACEi/sartans, 92.1% on dual antiplatelet therapy, 99.5% on statins, 16.1% on ezetimibe, and 9.9% on PCSK9 inhibitors. At multivariate regression analysis, heart rate, baseline creatinine values, and statin therapy were independent predictors of the composite endpoint all cause death, ACS recurrence/cardiac ischemia/angina, restenosis/intrastent thrombosis, while heart rate and statin therapy remained predictors of the composite endpoint death, ACS recurrence/cardiac ischemia/angina, restenosis/intrastent thrombosis, stroke/transient ischemic attack (TIA), heart failure (Figure 1). Conclusions Statin therapy confirmed their therapeutic role in secondary cardiovascular prevention protocols. The need for continuing long–term statin therapy after ACS is fundamental in order to ameliorate the prognosis of patients.

C59 HEART RATE AT DISCHARGE AS INDEPENDENT LONG–TERM PREDICTOR OF ALL–CAUSE MORTALITY IN PATIENTS WITH ACS: INSIGHTS FROM THE APULIA PONTE ACS STUDY

Abstract Background Heart rate is able to impact on the prognosis if patients with cardiovascular diseases. The aim of this study was to evaluate the impact of heart rate at discharge of patients with ACS and/or coronary revascularization on long–term follow–up Methods This was a subanalysis of the PONTE ACS study. The PONTE ACS study is a prospective, longitudinal, cohort study which enrolled patients who were discharged from HUB centres of ASL BARI after coronary revascularization and/or ACS. They underwent clinical evaluation at 30 days, 3, 6 and 1 year–follow–up. The data were collected after including the data in the electronic medical record of the PONTE ACS study. Anthropometric, clinical and pharmacological parameters, instrumental and laboratory examinations were included. Data were computed in order to evaluate the major determinants of all–cause mortality at one–year follow–up. Results We finally enrolled 2476 patients (77.4% male, mean age: 67.2±12.0 years). Pharmacological treatments were optimized during the follow–up visits. Heart rate at discharge was 65.5 ± 11.3 bpm. At univariate regression analysis, age, systolic and diastolic arterial pressure, body mass index, smoke habit, diabetes, hypertension, high–density lipoprotein and total cholesterol, creatinine, haemoglobin, fasting glycemia, left ventricle ejection fraction, heart rate, use of ACEi/sartans, statins, dual/triple anti–thrombotics were all related to all–cause mortality. Nevertheless, at multivariate Cox regression analysis, age (β coefficient: 0.07117 ± 0.01942, p = 0.0002), history of hypertension (1.4823 ± 0.7476, p = 0.0474), and heart rate (0.04409 ± 0.01278, p = 0.0006) remained related to the primary endpoint. Conclusions Heart rate confirmed to act as a long–term predictor of all–cause death in patients with ACS.

Presence of Five Chemotherapeutic Drugs in Breast Milk as a Guide for the Safe Use of Chemotherapy During Breastfeeding: Results From a Case Series.

Little is known about infant's safety of chemotherapy during breastfeeding where evidence is limited to a few case reports. This lack of knowledge has led to a general tendency to advise against breastfeeding during cytotoxic therapy despite the overwhelming benefits that breastfeeding offers to both the mothers and their children. In this case series, the presence of five chemotherapies in breast milk was determined. The aim was to obtain insight into the presence of these drugs in breast milk to inform and help clinicians in making informed decisions for women who want to breastfeed. Three patients collected 24-hour samples of breast milk every day for 1, 2, or 3weeks after chemotherapy, 210 in total. After determination of drug concentrations, the infant daily dose, relative daily infant dose (RID%) and cumulative RID were calculated. Cumulative RIDs in patients varied from 10% to values lower than 1%. Rich data allowed us to design a table which gives predictions on the amount of days that breast milk has to be discarded to reach cumulative RIDs below 5, 1, and 0.1% for each compound. For cyclophosphamide, paclitaxel, and carboplatin, cumulative RIDs below 1 or 0.1% are reached if breast milk is discarded for 1-3days after administration. This might suggest that breastfeeding in between cycles is an option. However, other pharmacological parameters should also be taken into consideration. For doxorubicin, also the levels of the active metabolite doxorubicinol need quantification. Similarly, breastfeeding during treatment with cisplatin might give substantial exposure and we advise caution.

Improving individualized prescription in patients with multimorbidity through medication review

BackgroundOlder patients tend to have multimorbidity, represented by multiple chronic diseases or geriatric conditions, which leads to a growing number of prescribed medications. As a result, pharmacological prescription has become a major concern because of the increased difficulties to ensure appropriate prescription in older adults. The study’s main objectives were to characterize a cohort of older adults with multimorbidity, carry out a medication review and compare the pharmacological data before and after the medication review globally and according to the frailty index.MethodsThis was a quasi-experimental (uncontrolled pre-post) study with a cohort of patients ≥ 65 years old with multimorbidity. Data were collected from June 2019 to October 2020. Variables assessed included demographic, clinical, and pharmacological data, degree of frailty (Frail-VIG index), medication regimen complexity index, anticholinergic and or sedative burden index, and monthly drug expenditure. Finally, a medication review was carried out by an interdisciplinary team (primary care team and a consultant team with a geriatrician and a clinical pharmacist) by applying the Patient-Centered Prescription model to align the treatment with care goals.ResultsFour hundred twenty-eight patients were recruited [66.6% women; mean age 85.5 (SD 7.67)]. The mean frail index was 0.39 (SD 0.13), corresponding with moderate frailty. Up to 90% of patients presented at least one inappropriate prescription, and the mean of inappropriate prescriptions per patient was 3.14 (SD 2.27). At the three-month follow-up [mortality of 17.7% (n = 76)], the mean chronic medications per patient decreased by 17.96%, varying from 8.13 (SD 3.87) to 6.67 (SD 3.72) (p < 0.001). The medication regimen complexity index decreased by 19.03%, from 31.0 (SD 16.2) to 25.1 (SD 15.1), and the drug burden index mean decreased by 8.40%, from 1.19 (SD 0.82) to 1.09 (SD 0.82) (p < 0.001). A decrease in polypharmacy, medication regimen complexity index, and drug burden index was more frequent among frail patients, especially those with severe frailty (p < 0.001).ConclusionsAn individualized medication review in frail older patients, applying the Patient-Centered Prescription model, decreases pharmacological parameters related to adverse drug effects, such as polypharmacy, therapeutical complexity, and anticholinergic and, or sedative burden. The benefits are for patients with frailty.