Doses Of Individual Drugs Research Articles

Targeted PHA Microsphere-Loaded Triple-Drug System with Sustained Drug Release for Synergistic Chemotherapy and Gene Therapy.

The combination of paclitaxel (PTX) with other chemotherapy drugs (e.g., gemcitabine, GEM) or genetic drugs (e.g., siRNA) has been shown to enhance therapeutic efficacy against tumors, reduce individual drug dosages, and prevent drug resistance associated with single-drug treatments. However, the varying solubility of chemotherapy drugs and genetic drugs presents a challenge in co-delivering these agents. In this study, nanoparticles loaded with PTX were prepared using the biodegradable polymer material poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx). These nanoparticles were surface-modified with target proteins (Affibody molecules) and RALA cationic peptides to create core-shell structured microspheres with targeted and cationic functionalization. A three-drug co-delivery system (PTX@PHBHHx-ARP/siRNAGEM) were developed by electrostatically adsorbing siRNA chains containing GEM onto the microsphere surface. The encapsulation efficiency of PTX in the nanodrug was found to be 81.02%, with a drug loading of 5.09%. The chemogene adsorption capacity of siRNAGEM was determined to be 97.3%. Morphological and size characterization of the nanodrug revealed that PTX@PHBHHx-ARP/siRNAGEM is a rough-surfaced microsphere with a particle size of approximately 150 nm. This nanodrug exhibited targeting capabilities toward BT474 cells with HER2 overexpression while showing limited targeting ability toward MCF-7 cells with low HER2 expression. Results from the MTT assay demonstrated that PTX@PHBHHx-ARP/siRNAGEM exhibits high cytotoxicity and excellent combination therapy efficacy compared to physically mixed PTX/GEM/siRNA. Additionally, Western blot analysis confirmed that siRNA-mediated reduction of Bcl-2 expression significantly enhanced cell apoptosis mediated by PTX or GEM in tumor cells, thereby increasing cell sensitivity to PTX and GEM. This study presents a novel targeted nanosystem for the co-delivery of chemotherapy drugs and genetic drugs.

Harnessing Pharmacogenomics in Clinical Research on Psychedelic-Assisted Therapy.

Psychedelics have recently re-emerged as potential treatments for various psychiatric conditions that impose major public health costs and for which current treatment options have limited efficacy. At the same time, personalized medicine is increasingly being implemented in psychiatry to provide individualized drug dosing recommendations based on genetics. This review brings together these topics to explore the utility of pharmacogenomics (a key component of personalized medicine) in psychedelic-assisted therapies. We summarized the literature and explored the potential implications of genetic variability on the pharmacodynamics and pharmacokinetics of psychedelic drugs including lysergic acid diethylamide (LSD), psilocybin, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), ibogaine and 3,4-methylenedioxymethamphetamine (MDMA). Although existing evidence is limited, particularly concerning pharmacodynamics, studies investigating pharmacokinetics indicate that genetic variants in drug-metabolizing enzymes, such as cytochrome P450, impact the intensity of acute psychedelic effects for LSD and ibogaine, and that a dose reduction for CYP2D6 poor metabolizers may be appropriate. Furthermore, based on the preclinical evidence, it can be hypothesized that CYP2D6 metabolizer status might contribute to altered acute psychedelic experiences with 5-MeO-DMT and psilocybin when combined with monoamine oxidase inhibitors. In conclusion, considering early evidence that genetic factors can influence the effects of certain psychedelics, we suggest that pharmacogenomic testing should be further investigated in clinical research. This is necessary to evaluate its utility in improving the safety and therapeutic profile of psychedelic therapies and a potential future role in personalizing psychedelic-assisted therapies, should these treatments become available.

Abstract 955: Double-targeting of pancreatic ductal adenocarcinoma (PDAC): Unveiling the potent combination of NMS-873 and BAY-876

Abstract Pancreatic ductal adenocarcinoma (PDAC) stands out as one of the most aggressive and challenging-to-treat cancers known. Consequently, the development of effective therapeutic strategies holds significant importance in enhancing patient outcomes. In contrast to single-drug treatments, combination therapies offer the potential for improved results by addressing multiple pathways. This approach not only reduces the likelihood of drug resistance but also encourages synergistic effects, all while permitting the use of lower individual drug doses, thus minimizing potential side effects. In this study, we subjected a panel of PDAC cell lines with varying degrees of sensitivity to a high-throughput combinatorial drug screen. Mitochondrial complex 1/p97 inhibitor NMS-873 was tested in combination with 95 other compounds, revealing remarkable synergy when paired with Glut1 inhibitor BAY-876. In order to affirm the validity of these findings, we conducted further experiments involving multi-dose drug combinations within long-term clonogenic assays. These supplementary investigations also demonstrated significant synergistic effects between BAY-876 and NMS-873, as quantified through the calculation of Bliss and Zip scores. Notably, this combination exhibited superior efficacy when confronting PDAC cell lines that are more resistant to NMS-873, highlighting the potential of this combination to overcome therapy resistance. To gain insights into the underlying mechanisms behind these outcomes, we performed a gene enrichment analysis which revealed that the more sensitive cell lines exhibited elevated rates of cell division, while the more resistant ones demonstrated heightened cRNA processing and increased metabolic activity, particularly in protein, phospholipid, and lipid synthesis. The combination of BAY-876 and NMS-873 presents a promising avenue for the targeted treatment of PDAC. This study underscores the remarkable synergy observed in mouse PDAC cell lines with a particular emphasis on the heightened efficacy against cell populations that are more resistant to NMS-873. These results warrant further investigation to elucidate the underlying molecular mechanisms and validate these findings in clinical settings. Citation Format: Emily Rita Eppinger, Christian Schneeweis, Dieter Saur. Double-targeting of pancreatic ductal adenocarcinoma (PDAC): Unveiling the potent combination of NMS-873 and BAY-876 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 955.

Abstract 7230: A novel platform for identifying therapeutic index in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) remains highly aggressive with a mere 12% 5-year survival rate, which underscores the urgent need for improved therapeutic approaches. The current standard of care primarily includes surgery and chemotherapy. However, existing therapies often result in severe side effects and offer limited success. The limitations are not only due to the development of treatment resistance but also due to the killing of normal cells, and as such a low therapeutic index. Targeted therapies aimed at the primary drivers of PDA, such as the KRASG12D mutation or the activated ErbB pathway, have shown promise in providing novel treatment options. We have previously demonstrated that combining targeted therapies, specifically KRASG12D and EGFR inhibitors, results in reduced tumor growth in both human and murine PDA organoid models in vitro. However, less is known about how these targeted therapies affect normal cells. Here, we are using co-cultures of normal pancreas and PDA organoids to create a platform that allows us to identify combinations of targeted therapies that can achieve a higher therapeutic index. Our goal is to identify treatment combinations that allow for the use of lower individual drug dose, while exhibiting enhanced anti-tumor efficacy and minimizing toxicities to normal organoids. This approach holds significant promise for improving patient outcomes and addressing the challenges associated with current PDA treatments. Citation Format: Vasiliki Pantazopoulou, Dannielle Engle. A novel platform for identifying therapeutic index in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7230.

Optimizing the Treatment of Invasive Candidiasis-A Case for Combination Therapy.

Invasive candidiasis is a rising global health threat with increasing incidence, persistently high mortality, and diminishing treatment options. Antifungal resistance has rapidly emerged and spread, with multidrug-resistant species deemed an urgent and serious threat. While acknowledging the key role of antifungal stewardship and infection control in curbing spread, we examine the role of antifungal monotherapy in driving resistance and the potential for combination therapy to prevent stress adaptation and emergence of drug resistance. In addition to its role in mitigating resistance, combination treatment may improve drug penetration, expedite fungal clearance, and allow lower, less toxic doses of individual drugs to be used. A growing body of laboratory-based evidence suggests that antifungal combinations can yield synergistic activity against Candida spp., including against frequently multidrug-resistant Candida auris. It is imperative to test these combinations in clinical trials, incorporating resistance end points as a marker of success.

Synergistic cytotoxicity of fludarabine, clofarabine, busulfan, vorinostat and olaparib in AML cells

Combinations of nucleoside analog(s) and DNA alkylating agent(s) are used for cancer treatment as components of pre-transplant regimens used in hematopoietic stem cell transplantation. Their efficacies are enhanced by combining drugs with different mechanisms of action, which also allows a reduction in the individual drug dosages and thus potentially in toxicity to the patient. We hypothesized that addition of SAHA and olaparib, an HDAC- and a PARP-inhibitor, respectively, to the established combination of fludarabine, clofarabine and busulfan would enhance AML cell cytotoxicity. Exposure of the AML cell lines KBM3/Bu2506, MV4-11, MOLM14 and OCI-AML3 to the 5-drug combination resulted in synergistic cytotoxicity with combination indexes < 1. Increased protein acetylation and decreased poly(ADP-ribosyl)ation were observed, as expected. Activation of apoptosis was suggested by cleavage of Caspase 3 and PARP1, DNA fragmentation, increased reactive oxygen species, and decreased mitochondrial membrane potential. The reduction in poly(ADP-ribosyl)ation was independent of caspase activation. Several proteins involved in DNA damage response and repair were downregulated, which may be contributing factors for the observed synergism. The increased phosphorylation of DNAPKcs suggests inhibition of its kinase activity and diminution of its role in DNA repair. A similar synergism was observed in patient-derived cell samples. These findings will be important in designing clinical trials using these drug combinations as pre-transplant conditioning regimens for AML patients.

Impact of undernutrition on the pharmacokinetics of chemotherapy in children with cancer: A systematic review.

This systematic review provides an overview of the effect of undernutrition on the pharmacokinetics of chemotherapy in children with cancer. PubMed, Embase, and Cochrane were searched to identify eligible studies. This study uses the definition for undernutrition from the World Health Organization and the Gomez classification. Four studies with a total of 668 children with cancer were included and n=121 (18%) were undernourished. Significant decreased clearance rates were found for vincristine in undernourished children compared to children with a normal nutritional status. Presenting outcomes only show significant changes in the pharmacokinetics of vincristine in undernourished children with cancer. However, data are scarce, groups were small, and none of the studies included severely undernourished children. In order to improve outcomes for (severely) undernourished children with cancer, more pharmacokinetic research is needed. The ultimate goal would be to develop subgroups, and ultimately individualized drug dosing in order to improve outcomes for children with cancer worldwide.

A pharmacokinetic analysis of amisulpride in adult Chinese patients with schizophrenia: Impact of creatinine clearance.

To develop a stable population pharmacokinetic (PPK) model of amisulpride and to investigate the effects of covariates on the pharmacokinetic parameters in adult Chinese patients with schizophrenia. This retrospective study was carried out using 168 serum samples from 88 patients collected during routine clinical monitoring. Covariates recorded included demographic parameters (gender, age, weight), clinical parameters (serum creatinine, creatinine clearance), and intake of co-medications. The amisulpride PPK model was established using a nonlinear mixed effects modeling (NONMEM) approach. Goodness-of-fit (GOF) plots, bootstrap validation (1,000 runs), and normalized prediction distribution error (NPDE) were used in the evaluation of the final model. A one-compartment model with first-order absorption and elimination was developed. The population estimates for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 32.6 L/h and 391 L, respectively. Estimated creatinine clearance (eCLcr) was a significant covariate for CL/F. The established model was: CL/F = 32.6 × (eCLcr/114.3)0.485 (L/h). The stability of the model was confirmed using GOF plots, bootstrap, and NPDE. Creatinine clearance is a major covariate which is positively correlated with CL/F. Therefore, additional dose adjustments of amisulpride may be required on the basis of eCLcr. An ethnic difference may exist in the pharmacokinetics of amisulpride, but further research is needed in order to confirm this possibility. The PPK model of amisulpride for adult Chinese schizophrenic patients established here using NONMEM, is potentially an important tool for individualizing drug dosage and therapeutic drug monitoring.

Poor Neonatal Adaptation After Antidepressant Exposure During the Third Trimester in a Geographically Defined Cohort

ObjectiveTo examine the associations between antidepressant exposure during the third trimester of pregnancy, including individual drugs, drug doses, and antidepressant combinations, and the risk of poor neonatal adaptation (PNA). Patients and MethodsThe Rochester Epidemiology Project medical records-linkage system was used to study infants exposed to selective serotonin reuptake inhibitors (SSRIs; n=1014), bupropion, (n=118), serotonin-norepinephrine reuptake inhibitors (n=80), antidepressant combinations (n=20), or other antidepressants (n=22) during the third trimester (April 11, 2000-December 31, 2013). Poor neonatal adaptation was defined based on a review of medical records. Poisson regression was used to examine the risk of PNA with serotonergic antidepressant and drug combinations compared with that with bupropion monotherapy as well as with high- vs standard-dose antidepressants. When possible, analyses were performed using propensity score (PS) weighting. ResultsForty-four infants were confirmed cases of PNA. Serotonin-norepinephrine reuptake inhibitor monotherapy, antidepressant combinations, and paroxetine monotherapy were associated with a significantly higher risk of PNA than bupropion monotherapy in unweighted analyses. High-dose SSRI exposure was associated with a significantly increased risk of PNA in unadjusted (relative risk, 2.61; 95% confidence interval, 1.35-5.04) and PS-weighted models (relative risk, 2.29; 95% confidence interval, 1.17-4.48) compared with standard-dose SSRI exposure. The risk of PNA was significantly higher with high-dose paroxetine and sertraline than with standard doses in the PS-weighted analyses. The other risk factors for PNA included maternal anxiety disorders. ConclusionAlthough the frequency of PNA in this cohort was low (3%-4%), the risk of PNA was increased in infants exposed to serotonergic antidepressants, particularly with SSRIs at higher doses, during the third trimester of pregnancy compared with that in infants exposed to standard doses. Potential risk factors for PNA also included third-trimester use of paroxetine (especially at higher doses) and maternal anxiety.

Variation in missed doses and reasons for discontinuation of anti-tuberculosis drugs during hospital treatment for drug-resistant tuberculosis in South Africa.

Updated World Health Organization (WHO) treatment guidelines prioritize all-oral drug-resistant tuberculosis (DR-TB) regimens. Several poorly tolerated drugs, such as amikacin and para-aminosalicylic acid (PAS), remain treatment options for DR-TB in WHO-recommended longer regimens as Group C drugs. Incomplete treatment with anti-TB drugs increases the risk of treatment failure, relapse, and death. We determined whether missed doses of individual anti-TB drugs, and reasons for their discontinuation, varied in closely monitored hospital settings prior to the 2020 WHO DR-TB treatment guideline updates. We collected retrospective data on adult patients with microbiologically confirmed DR-TB between 2008 and 2015 who were selected for a study of acquired drug resistance in the Western Cape Province of South Africa. Medical records through mid-2017 were reviewed. Patients received directly observed treatment during hospitalization at specialized DR-TB hospitals. Incomplete treatment with individual anti-TB drugs, defined as the failure to take medication as prescribed, regardless of reason, was determined by comparing percent missed doses, stratified by HIV status and DR-TB regimen. We applied a generalized mixed effects model. Among 242 patients, 131 (54%) were male, 97 (40%) were living with HIV, 175 (72%) received second-line treatment prior to first hospitalization, and 191 (79%) died during the study period. At initial hospitalization, 134 (55%) patients had Mycobacterium tuberculosis with resistance to rifampicin and isoniazid (multidrug-resistant TB [MDR-TB]) without resistance to ofloxacin or amikacin, and 102 (42%) had resistance to ofloxacin and/or amikacin. Most patients (129 [53%]) had multiple hospitalizations and DST changes occurred in 146 (60%) by the end of their last hospital discharge. Incomplete treatment was significantly higher for amikacin (18%), capreomycin (18%), PAS (17%) and kanamycin (16%) than other DR-TB drugs (P<0.001), including ethionamide (8%), moxifloxacin (7%), terizidone (7%), ethambutol (7%), and pyrazinamide (6%). Among the most frequently prescribed drugs, second-line injectables had the highest rates of discontinuation for adverse events (range 0.56-1.02 events per year follow-up), while amikacin, PAS and ethionamide had the highest rates of discontinuation for patient refusal (range 0.51-0.68 events per year follow-up). Missed doses did not differ according to HIV status or anti-TB drug combinations. We found that incomplete treatment for second-line injectables and PAS during hospitalization was higher than for other anti-TB drugs. To maximize treatment success, interventions to improve person-centered care and mitigate adverse events may be necessary in cases when PAS or amikacin (2020 WHO recommended Group C drugs) are needed.

Progress in Analytical Techniques for Remogliflozin Etabonate, Vildagliptin And Metformin Hydrochloride: A Recently, Approved FDC

Background:Fixed-dose combinations (FDCs) are renowned formulations that contain two or more drugs pooled in a single dosage form. Their recognition is justified due to several advantages, such as impending therapeutic efficacy, reducing the episodes of adverse drug effects, having pharmacokinetic advantages, reducing pill burden, reducing the dose of individual drugs, and decreasing drug resistance development.Objective:Recently, an FDC tablet of remogliflozin etabonate (100 mg), vildagliptin (50 mg), and metformin HCl (500/1000 mg) has been approved for the treatment of type 2 diabetes mellitus. No analytical method has been reported thus far for this newly approved combination.Methods:Thus, this review collected and simplified information on reported analytical techniques and physicochemical and biological properties for the above-cited FDCs. The authors have explored various authenticated scientific journals, and simplified information was presented to meet the objectives.Results:The reported methods are spectroscopy (40%, 20% &amp; 33%), HPTLC (10%, 14% &amp; 20%), HPLC (50%, 49% &amp; 41%), hyphenated techniques (Nil, 14% &amp; 5%) and electrophoresis methods (Nil, 2% &amp; 1%) for remogliflozin etabonate, vildagliptin and metformin HCl, respectively.Conclusion:Such extensive data would be useful to analysts in developing an analytical method for the analysis of the recently approved FDCs

Progress in Quantitative Methods for Azelnidipine and Chlorthalidone: An Analytical Basis for a Recently Approved FDC

Backgroound: Products with multiple active substances mixed in a single dosage form are fixed-dose combinations. These are justified for a variety of reasons. These include a) increasing therapeutic efficacy, b) lowering adverse drug effects, c) pharmacokinetic advantages, d) lowering pill load, e) lowering individual drug doses, and f) lowering drug resistance development. Objective: A recently approved fixed dose combination of azelnidipine (8 mg) and chlorthalidone (6.25 or 12.5 mg) is indicated to treat hypertension. Individual quantification methods for azelnidipine and chlorthalidone are available, but no practical and acceptable analytical approach for their combination has been documented. As a result, the goal of this literature review was to gather information on the numerous analytical instrumental approaches utilized to quantify azelnidipine and chlorthalidone in diverse matrices individually. The scientific community could use this information to design a new analytical method for analysing the recently approved combination. Methods: Authors have explored various scientific databases to obtain information on analytical methods. Results: The methods listed for azelnidipine and chlorthalidone are spectroscopy, high-performance liquid chromatography, hyphenated techniques, high-performance thin-layer chromatography, thin-layer chromatography, and a few other approaches. For azelnidipine and chlorthalidone, there were 26 and 46 research papers reported, respectively.

RF07 | PSUN356 Synergistic Combination of HSP90 and PI3K inhibitors in Adrenocortical Cancer

Abstract Adrenocortical cancer (ACC) is a rare and aggressive cancer (0.5-2 cases/ million/ year) with a poor 5-year survival (&amp;lt;40%). Most patients inevitably succumb to the wide-spread metastasis because of the lack of effective systemic treatment options or to complications from uncontrolled hypercortisolism. Therefore, it is critically important to identify new effective treatments that can be readily used in a clinical trial. In this direction, we identified a potent synergistic combination of Heat Shock Protein 90 (HSP90) and PI3K inhibitors via quantitative high-throughput drug screening (qHTS) for ACC, using a pharmaceutical library comprised of ∼5000 drugs (FDA approved or investigational), and evaluation of drug synergy by a computerized drug combination matrix analysis. The synergistic efficacy of HSP90 inhibitor STA9090 and PI3K inhibitor, PIK75 was validated in vitro, in ACC cell lines H295R and SW13, by proliferation assay, which also determined the most efficacious doses of individual and combinatorial drugs. The drug combination significantly induced apoptosis and disintegrated the 3D-ACC spheroids as compared to the individual drugs, with a simultaneous upregulation of apoptotic protein markers (cleaved-Caspase3, cleaved-PARP), inhibition of the phosphorylation of PI3K pathway members (AKT1, mTOR, S6K, 4EB1 and GSK3α/β), and alteration in the G2/M phase of the cell cycle, in ACC cells. The synergetic effect of the drug combination was also effective in reducing the metastatic potential as revealed by invasion/migration assay, which was confirmed by the downregulation of the mesenchymal protein (Vimentin, N-cadherin, SNAIL and Zeb1) markers. Consistent with our data, observations from the gene expression data from The Cancer Genome Analysis (TCGA) &amp; Gene Expression Omnibus (GEO) databases, revealed significant mRNA overexpression of HSP90AA1, HSP90AB1 HSP90B1 and its clients AKT2, CDK1, CDK4, NR3C1 indicating both HSP90 and PI3K/AKT pathways are highly activated in ACC cohorts. Overexpression and a positive correlation of mesenchymal markers TWIST1, ZEB1, VIM with HSP90AB1 and PI3KCA, in GEO and TCGA respectively, was consistent with the invasive potential of the ACC cells. In conclusion, our studies on the combination of HSP90 and PI3K inhibitors demonstrated a promising preliminary synergistic efficacy by inhibiting proliferation and epithelial-to-mesenchymal transition of ACC. Our findings can lead to development of an efficient mechanism-specific novel combination therapy that can be expedited to clinical trial in advanced ACC patients. Presentation: Saturday, June 11, 2022 1:12 p.m. - 1:17 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Type and Severity of Mental Illness and Participation in Colorectal Cancer Screening

The effectiveness of colorectal cancer screening programs depends on the participation rate. This study examined the association between type and severity of mental illness and colorectal cancer screening participation. Between 2012 and 2017, a total of 46,919 individuals were invited to sigmoidoscopy screening in Norway, and 70,019 were invited to fecal immunochemical testing. In 2022, logistic regression was used to evaluate the association between the use of antipsychotics, anxiolytics, hypnotics, and antidepressants in the year preceding the screening invitation and screening participation, adjusted for demographic and socioeconomic factors. Defined daily doses of individual drugs were used to assess dose‒response relationships. Overall, 19.2% (24.8% of women, 13.4% of men) of all invitees used at least 1 psychotropic medication. Nonparticipation in the 2 arms combined was associated with the use of anxiolytics (60.7% in users vs 43.2% in nonusers; OR=1.53; 95% CI=1.45, 1.62) and antipsychotics (64.3% vs 43.8%; OR=1.41; 95% CI=1.30, 1.53) and increased with higher doses for both drugs. Hypnotics and antidepressants were only weakly associated with nonparticipation in higher doses. Participation rates were 57.3%, 52.3%, 42.9%, and 35.4% in those prescribed 0, 1, 2, and 3-4 classes of psychotropic medications, respectively. The associations between the use of psychotropic medications and nonparticipation were similar for the 2 screening tests. These findings show significant disparities in colorectal cancer screening participation for individuals with mental illness, independent of the screening method. Moreover, screening participation varied depending on the type and severity of mental illness. Targeted interventions are warranted to ensure that people with mental illness are supported to access the benefits of colorectal cancer screening.

Application of user-centered co-design principles to address barriers in therapeutic drug monitoring.

Different software applications have been developed to support healthcare professionals in individualized drug dosing. However, their translation into clinical practice is limited, partly because of poor usability and integration into workflow, which can be attributed to the limited involvement of healthcare professionals in the development and implementation of drug dosing software. This study applied co-design principles to inform the design of a drug dosing software to address barriers in therapeutic drug monitoring (TDM) using vancomycin as an example. Three workshops (face-to-face and online) were conducted by design researchers with pharmacists and prescribers. User journey storyboards, user personas, and prototyping tools were used to explore existing barriers to practice and opportunities for innovation through drug dosing software design. A prototype of the software interface was developed for further evaluation. Healthcare professionals (11 hospital pharmacists and 6 prescribers) with ≥2 years of clinical experience were recruited. Confidence and software usability emerged as the main themes. Participants identified a lack of confidence in vancomycin dosing and pharmacokinetic understanding and difficulty in accessing practice guidelines as key barriers that could be addressed through software implementation. Accessibility to information (e.g., guidelines and pharmacokinetic resources) and information presentation (e.g., graphical) within the dosing software were dependent on the needs and experience of the user. A software prototype with a speedometer-dial visual to convey optimal doses was well received by participants. The perspectives of healthcare professionals highlight the need for drug dosing software to be user-centred and adaptable to the needs and workflow of end users. Continuous engagement with stakeholders on tool usability, training, and education is needed to promote the implementation in practice.

Comprehensive Review of the Marketed Antiulcer Polyherbal Formulations

An imbalance in the aggressive factors and protective factors in the gastrointestinal tract leads to peptic ulcers. Modern medicinal prescriptions for ulcers involve the use of allopathic drugs. However, several disadvantages, such as side effects, discordancy, and altered physiological aspects, have led to the quest for alternative safer medications. The use of herbs to treat ulcers has been practiced for decades in Ayurveda. A combination of such herbs, known as polyherbal formulation, shows several advantages like synergistically augmented beneficial effects, better patient compliance, and reduction in dose of individual drugs without compromising the therapeutic effects. In recent years, this valuable traditional knowledge of the medicinal values of herbs, along with current value-added developments, has ensured the usage of improved Ayurvedic medicine in a milieu of treatments. In the last two decades, many polyherbal formulations have been developed and evaluated for their antiulcer potential. The advancements in analytical methods have even led to the isolation of the phytoconstituents from crude herbal drugs, and their benefits in therapeutics have been studied. The core aim of the current review is to enlighten the comprehensive overview of the composition of some marketed antiulcer polyherbal formulations and the preclinical models to prove their gastroprotective potentials based on scientific findings.

Already low drug dose antagonism of the renin-angiotensin aldosterone system decreases 1-year mortality and rehospitalization in old heart failure patients

AimsHospitalization for heart failure treatment (HHF) is an incisive event in the course of HF. Today, the large majority of HHF patients is ≥ 65 years and discharge HF drugs are most often not applied at dose levels acknowledged to provide prognostic benefit. This study therefore aims to investigate the treatment effect size of discharge HF drugs in old HHF patients. MethodsDrugs are analyzed according to pharmacological class. Individual discharge HF drug dose is reported as percentage of guidelines-recommended target dose. Primary endpoint was 1-year all-cause mortality (ACM) after discharge; the secondary endpoint combined 1-year ACM and first cardiovascular hospitalization within 1 year after discharge. Comparison between 65–80 years and > 80 years old study participants tested the relative treatment effect size as a function of respective age group. ResultsThe 875 consecutive HHF patients had a median age of 82 years [76–87 years]; 48.6 % were females. Betablocker and diuretic treatment did not change the incidence of endpoints. Inhibition of the renin-angiotensin system (RASi), when compared to no treatment, decreased the incidence of endpoints both at the 1–25 % and the > 25 % target dose level. Antagonists of the mineralocorticoid receptor (MRA), when compared to no treatment, decreased the secondary endpoint at the 1–25 % target dose level but not at the > 25 % target dose level. The relative treatment effect size of RASi or MRA corresponded between the age strata for both endpoints. ConclusionLow-dose RASi and MRA had beneficial effects in these old HHF patients.

Prevention Of Drug-Induced Osteonecrosis Of The Jaw In Cancer Patients

The occurrence of drug-induced osteonecrosis of the jaw in cancer patients treated using bone-modifying medications (bisphosphonates and denosumab) is a highly relevant research problem studied by dentists, maxillofacial surgeons, and oncologists. Despite the large number of publications, practical approaches to preventing drug-induced osteonecrosis of the jaw remain to be developed, which is confirmed by the increasing prevalence and severity of the clinical course of the disease. In this article, we review the most significant works and position papers published in Russia and abroad over the past 10 years, as well as the authors’ scientific and clinical experience, in order to identify key reasons behind the ineffective prevention of drug-induced osteonecrosis of the jaw in cancer patients and to suggests possible solutions. Questions concerning the legal protection of patients and clinicians in relation to this complication are discussed. Most recent achievements in the field of laboratory diagnostics and risk assessment of drug-induced osteonecrosis of the jaw in cancer patients, including the determination of bone metabolism markers, are presented. The following criteria for the safe use of bisphosphonates and denosumab in cancer patients were identified: dental screening; clinical and laboratory monitoring; individualizing drug dosage, duration and withdrawal regimens; application of an interdisciplinary approach.

The EHA Research Roadmap: Malignant Lymphoid Diseases.

The EHA Research Roadmap: Malignant Lymphoid Diseases.

Determination of Guanfacine in Oral Fluid and Serum of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Short Communication.

Guanfacine, a selective α2A-adrenoreceptor agonist, is a second-line medication for treating children and adolescents with attention-deficit/hyperkinetic disorder. The dosage administered as milligram per body weight to balance the potential benefits and risks of treatment. Therapeutic drug monitoring (TDM) is useful for identifying a patient's therapeutic window to optimize individual drug dosing and reduce the risk of adverse drug reactions. However, in children and adolescents, intravenous sample collection is especially stressful and thus remains a primary challenge, restricting the use of TDM. Therefore, evaluating alternative specimens to facilitate TDM is a worthwhile task. The aim of this study was to assess the feasibility of using oral fluid for TDM of guanfacine in children and adolescents. In this article, 9 patients (median age 8.1 years; 6 boys and 3 girls) undergoing treatment with guanfacine were included. Simultaneously collected oral fluid and serum samples were deproteinized using methanol containing a stable isotope-labeled internal standard before the determination of guanfacine by liquid chromatography-tandem mass spectrometry. Pearson correlation and paired t test were used for statistical analysis. The mean serum guanfacine concentration was 3 times higher than that detected in oral fluid (7.47 ng/mL versus 2.36 ng/mL; t (8) = 5.94; P < 0.001). A strong positive linear correlation (r = 0.758, P = 0.018) was identified between oral fluid and serum concentrations. A strong but nonsignificant negative correlation (r = -0.574, P = 0.106) was detected between the oral fluid pH and oral fluid-to-serum concentration ratio. The strong correlation between oral fluid and serum concentration and the probable small effect of oral fluid pH on oral fluid-to-serum concentration ratio supports guanfacine as a suitable candidate for TDM in oral fluid.