Dosing Compliance Research Articles

Clinical Application of Equivalent Uniform Dose in Intensity-Modulated Rotational Radiotherapy Based on Eclipse TPS

To investigate the application of equivalent uniform dose (EUD) in intensity-modulated rotational radiotherapy and to explore optimization methods for improving the quality of modulated treatment plans. The impact of the parameter a in the EUD formula on the characteristics of the EUD curve was analyzed using Python. Thirty cases of head and neck tumors, thoracic tumors, and pelvic tumors were randomly selected for treatment planning. Dose optimization for the target area and organs at risk were performed using a physics-based optimization approach or an optimization approach that combines physical constraints with the EUD function. The dose distribution and compliance with constraints of the two groups of plans were compared, while also observing the effect of different values of a on the planning outcomes. The impact of the value of a on the changes in EUD curve characteristics was consistent with its impact on the results of EUD plan optimization. When -15≤ a≤-5, the dose distribution in the target area was more uniform; when 1≤ a≤7, the effect on the uniform dose and low-dose regions in organs at risk was more noticeable; when 10≤ a≤30, the effect of constraining the high-dose regions in organs at risk was more pronounced, with the EUD for the target area and organs at risk exhibiting different expressions under different a values. The study also found that the target dose distribution and the protection of organs at risk in the EUD optimization group were better than those in the physical optimization group only. The a-value has a significant impact on the, the dose distribution in the target area and the organ at risk, providing a reference for the setting of a-value while using EUD to optimize the intensity modulation plan. The using of EUD optimization method can not only achieve excellent dose distribution in the target area, but also significantly reduce the normal tissue dose and the probability of complications, which has certain clinical application value.

Dose compliance of estramustine phosphate in neoadjuvant chemohormonal therapy combined with degarelix acetate predicts the biochemical recurrence in patients with very high-risk prostate cancer who underwent robot-assisted radical prostatectomy.

The objective of this study is to evaluate the safety and efficacy of neoadjuvant degarelix acetate and low-dose estramustine phosphate for high-/very high-risk prostate cancer. Overall, 187 patients diagnosed with National Comprehensive Cancer Network high-/very high-risk cTanyN0M0 localized prostate cancer who consented to undergo robot-assisted radical prostatectomy after receiving neoadjuvant chemohormonal therapy for 6 months were prospectively enrolled between December 2017 and March 2023. Adverse events, perioperative and histopathological outcomes, and biochemical recurrence-free survival rates were examined. Survival analysis compared the estramustine phosphate completion and reduction groups. Thirty-six patients discontinued neoadjuvant therapy in <5 months owing to adverse events (n = 34) or other reasons (n = 2). Eleven were excluded for being in the postoperative castration range. Of the 140 patients who underwent surgery, 124 continued with two tablets of estramustine phosphate and 16 with one tablet. Overall, 82 patients were very high-risk. Histopathological outcomes were significantly worse in the very high-risk group than those in the high-risk group. Very high-risk status and estramustine phosphate reduction were significant factors in biochemical recurrence in multivariate analysis. The biochemical recurrence-free survival rate in very high-risk patients was significantly lower in the estramustine phosphate dose reduction group than in the completion group but not significant in high-risk patients. Major adverse events were anemia (n = 174), elevated transaminase levels (n = 68), and deep vein thrombosis (n = 24). Severe adverse events included acute coronary syndrome (n = 4) and pulmonary embolism (n = 3). Dose compliance with estramustine phosphate predicted biochemical recurrence in patients with very high-risk prostate cancer undergoing robot-assisted radical prostatectomy with neoadjuvant chemohormonal therapy.

The public health impact of recombinant herpes zoster vaccination in adults over 50 years in Spain

ABSTRACT The recombinant zoster vaccine (RZV) is included in the Spanish National Immunisation Programme for adults 65 years of age (years), with a potential progressive catch-up program for adults 66–80 years, starting with 80 years. However, the risk of herpes zoster (HZ) increases significantly from 50 years. We estimated the public health impact (PHI) of vaccinating adults ≥50 years in Spain versus no vaccination, using a Markov model adapted to the Spanish setting. The model simulated a hypothetical ≥50 years cohort over a lifetime, with inputs from Spanish publications, databases, or publications from other countries where Spanish data were unavailable. Base case inputs included 67.7% RZV coverage and 61.1% second dose compliance. Outputs included clinical outcomes avoided, healthcare resource use avoided, and number-needed-to-vaccinate (NNV) to prevent one HZ case. Deterministic (DSA) and probabilistic sensitivity analyses (PSA) were also conducted. The model estimated that, compared with no vaccination, vaccinating adults ≥50 years in Spain (N = 19,850,213) with RZV could prevent 1,533,353 HZ cases, 261,610 postherpetic neuralgia episodes, 274,159 other complications, and 138 deaths through the cohorts’ remaining lifetime, mostly in the 50–59 years cohort. Furthermore, 3,500,492 primary care visits and 71,156 hospitalizations could be avoided, with NNV = 9 to prevent one HZ case. DSA predicted NNV = 7 to prevent one HZ case when second dose compliance was increased to 100%. PSA demonstrated ≥200,000 and ≥1,400,000 cases could be prevented in 86.9% and 18.4% of simulations, respectively. Starting RZV from 50 years could therefore prevent a substantial number of HZ cases and complications. Increasing RZV coverage and second dose compliance could further alleviate PHI of HZ.

Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial.

Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.

Diabetes Management and Problems Experienced by Patients with Type 1 Diabetes Mellitus During the COVID-19 Pandemic: A Qualitative Study

Objective: A study was conducted to obtain information about problems in diabetes management experienced by patients with type 1 diabetes mellitus during the coronavirus disease (COVID-19) pandemic. Materials and Methods: In this qualitative study, in-depth interviews were carried out with 43 patients with type 1 diabetes mellitus (25 women, 18 men) aged 18-34 years who volunteered to participate. Each interview lasted 30 to 35 minutes. The conventional content analysis of data was performed using Graneheim &amp;amp; Lundman method. Results: The mean age of the participants was 26.05±8.01 years, the mean HbA1c level was 9.57±2.57%, and the duration of diabetes was 8.70±5.22 years. The study revealed 7 problem areas related to the patients’ diabetes management during the COVID-19 pandemic: blood glucose control, dietary adherence, insulin dose adjustment, exercising, psychosocial problems, sleep problems, and compliance with COVID-19 preventive measures. Conclusion: The study's results showed that during the COVID-19 pandemic, patients with type 1 diabetes mellitus experienced difficulties in diabetes management and negatively impacted psychosocially.

Abstract LB_A13: Phase 1 dose expansion results of CYT-0851, a monocarboxylate transporter (MCT) inhibitor, in combination with capecitabine (cape) in platinum-resistant ovarian cancer

Abstract Background: The MCT inhibitor CYT-0851 potently inhibits MCT1, has activity against MCT4, and blocks lactate transport resulting in cell death in glycolytic cancer cells. In an in vitro CRISPR screen, thymidylate synthetase was a significant hit in 2 resistant cell models, sensitizing them to CYT-0851. Follow-up in vitro combination studies showed that CYT-0851 synergized with 5-FU to inhibit cancer cell growth. Monotherapy clinical activity of CYT-0851 has been reported previously in lymphoma and solid tumors. In the phase 1 dose escalation trial of CYT-0851 plus cape, 400 mg was identified as the recommended phase 2 dose. In three phase 2 trials, cape had a RECIST response rate of 5-8% in ovarian cancer. Methods: An expansion cohort of 10 patients (pts) with platinum resistant advanced ovarian cancer were treated with CYT-0851, 400 mg QD in combination with cape, 1000 mg/m2 PO BID x 14 days every 21 days and were evaluable. One additional pt treated at the 300 mg dose level was evaluable and added to the analysis. The primary objective was safety, and secondary objectives were pharmacokinetics and preliminary anti-tumor activity by RECIST. Results: As of Aug 21, 2023, 11 pts were treated and evaluable, 9 white, 1 African American black, and 1 American Indian or Alaskan native, with a median age of 64 (range 52-76). Median prior therapies were 6 (range 2-14). All but one had 3 or more prior therapies. Median CYT-0851 dose compliance with continuous daily dosing was 99% (range 91– 100%). There were no treatment discontinuations or CYT-0851 dose reductions for treatment related adverse events. 7 pts (64%) experienced a treatment-related adverse event, all were Grade 1-2. There were no grade 3+ treatment related adverse events. The most common related AEs were fatigue reported in 5 pts (46%), and decreased appetite, diarrhea, nausea, palmar-plantar erythrodysaesthesia syndrome and vomiting, each reported in 2 patients (18%). Exposure of CYT-0851 in combination with capecitabine exhibits dose proportional behavior and was similar between combination therapy and monotherapy. One pt had a confirmed PR with progression on day 294, and 2 additional pts achieved a PR that has not been confirmed yet, with treatment ongoing on day 113 and 41. 7 pts had SD, and one patient PD as best response. The disease control rate was 91%. 5 Pts discontinued for progressive disease with a median of 133 days of treatment (range 43-300), and 2 withdrew consent on days 131-134. 4 patients continue therapy on days 42,47,106, and 113. Median PFS was 170 days (95% CI 79-NA). Conclusions: The oral outpatient combination of CYT-0851 and cape has demonstrated an acceptable safety and tolerability profile without any unanticipated toxicities at clinically active doses. The disease control rate of 91% and unconfirmed response rate of 27% in refractory platinum resistant ovarian cancer is promising and warrants further exploration. Furthermore, this regimen should be evaluated in other tumor types commonly treated with 5-FU, including breast and colorectal cancer. Citation Format: Elizabeth Swisher, Gerald Steven Falchook, Pamela N. Munster, Nina Beri, Kathleen N. Moore, Timothy A. Yap, David R. Spigel, Susan Doleman, William D. Bradley, Thomas J. O'Shea, Markus F. Renschler, Ryan C. Lynch. Phase 1 dose expansion results of CYT-0851, a monocarboxylate transporter (MCT) inhibitor, in combination with capecitabine (cape) in platinum-resistant ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A13.

Assessment of patient knowledge, practice and adverse events of insulin administration and storage techniques in patients with diabetes

Diabetes mellitus is a group of metabolic disorder characterised by hyperglycaemia. For effective therapy, correct injection procedures, adequate storage, insulin dose adjustment, meal timing, site rotation, and compliance. The aim of this work is to assess the knowledge and practice of insulin administration and storage techniques in diabetes patients. It is a survey based cross sectional study conducted through both online and offline modes among diabetic patients consuming insulin in Ernakulam district. 213 cases were included and it consist of diabetic patients on insulin therapy. About 54.4% of patients were males and 45.6% patients were females. Majority 57.3% experienced hypoglycaemia and 17.3% never experienced it. 51.6% patients were educated by nurse, 25.6% by doctors and only 17.6% were educated by pharmacist. The study presented an insight into the practices of insulin administration and awareness to the diabetic patients, study also extended to other health care professionals in the society.

All-in-One Online Radiotherapy for Nasopharyngeal Carcinoma: Preliminary Results of Treatment Time, Contouring Accuracy, Treatment Plan Quality and Patient Compliance

To explore the feasibility of Fan-beam CT (FBCT)-based all in one (AIO) online workflow for nasopharyngeal carcinoma (NPC) in radical radiotherapy setting, and to preliminarily describe the timing of different steps in the process, contouring accuracy of regions of interest (ROIs), target coverage, organs at risk (OARs) dose and patient compliance. From March 16, 2022 to January 04, 2023, 25 NPC patients (22/25 diagnosed as phase III/IV disease according to 8th edition of the AJCC/UICC staging system) consecutively treated with AIO radiotherapy were prospectively enrolled. All patients received mask fixation and MRI simulation scan in advance. Primary gross tumor volume (GTVp) of nasopharynx was automatically delineated by AI and edited manually on MRI images. AIO online workflow started with an integrated KV-level CT in a CT-integrated linear accelerator. After that GTVp was registrated to CT images and other ROIs was contoured automatically and then modified manually as needed. Subsequently automatic treatment plan was calculated and optimized until the dose of target and OARs was evaluated satisfactory by physicians and physicists. Finally, treatment was delivered using volumetric modulated arc treatment (VMAT), with prescribed dose of 6996 cGy/ 33 fractions to the GTVp. Twenty-four patients (24/25, 96%) completed the AIO radiotherapy workflow successfully, with average treatment time of 28.3 min (range: 19.9-42.4 min). the AI-assisted ROIs automatically contouring took 1.55 min in average (range: 1.32-1.77 min), with an average DICE of 97.7% compared with modified contouring, and the average DICE was 95.7% for clinical tumor volume 1 (CTV1), 88.6% for CTV2, 73.6% for GTVn (cervical lymph node), 99.3% for 30 OARs. The automatic treatment plan averagely needed 3.5 min, and the pass rate of radiotherapy planning was 91.7% (22/24). The target coverage for PTVs for GTVp, CTV1, and CTV2 was 99.3%, 99.8%, 98.0% respectively. As for the dose of OARs, the average Dmax of brainstem was 5,583cGy; the Dmax of spinal cord was 3,467cGy; the Dmean of parotid was 3,285 cGy. The average monitor units of all patients was 643 MU and the delivery took 2.93 min. Patient compliance with respect to AIO workflow and total treatment time was excellent. The AIO online radiotherapy was promising for NPC patients, with clinically acceptable AI assisted ROIs contouring and treatment planning, as well as favorable patient compliance to the AIO online workflow.

High coverage and adherence to dose intervals of the national school-based HPV vaccination program in Sweden during 2012–2019

BackgroundClose monitoring of vaccination coverage is important for cervical cancer prevention efforts. The study aims to describe the HPV vaccination coverage by dose in girls eligible for HPV vaccination within Sweden’s childhood immunization program and provide an estimate on dose timing compliance. MethodsVaccination records between 2012 and March 2019 were obtained for girls born in 2000–2006 from the vaccination registers in Sweden. The mid-time population counts for the respective birth cohorts were taken as the denominator. Full-dose coverage and coverage with at least one dose of the vaccine were calculated within the two-dose and three-dose regimen, by region. Dose compliance was calculated within the two-dose regimen. ResultsVaccination coverage with at least one dose of the vaccine was >80% within birth cohorts 2001–2006. Full-dose coverage within a two-dose and three-dose regimen were 73.4% in birth cohorts 2004–2005, and 56.3% in birth cohorts 2000–2001, respectively. Little variation was observed in vaccination coverage between regions. Dose completion was 91.8%, and 72.8% in girls that initiated a two-dose and three-dose regimen, respectively. Among girls receiving a two-dose regimen, 93.0% received the second dose 6–12 months after dose one. DiscussionIn conclusion, high levels of HPV vaccination coverage were observed with little variation between regions. Dose timing compliance was particularly high in the two-dose regimen. To fully benefit from the impact of HPV vaccination, it will be important to further push the vaccination coverage and reach the girls that do not or partially engage with HPV vaccination.

Auto-Substitutions to Optimize Perioperative Antimicrobial Prophylaxis: Pre-Post Intervention Study.

Appropriate administration of perioperative antibiotics can prevent antimicrobial resistance, adverse drug events, surgical site infections, and increased costs to the health care system for many surgeries in Otolaryngology-Head and Neck Surgery (OHNS). The objective of the study is to achieve 90% compliance with evidence-based perioperative antibiotic prophylaxis guidelines among elective surgical procedures in OHNS. The pre-intervention group consisted of patients undergoing elective surgical procedures in the 13 months prior to the interventions (September 2019-2020) whereas the post-intervention group comprised patients undergoing elective procedures during the 8 months following the implementation (October 2020-May 2021). The 4 Es of knowledge translation and the Donabedian framework were used to frame the study. Components of the intervention included educational grand rounds and automatic substitutions in electronic health records. In June 2021, a survey of staff and residents assessed the self-reported perception of following evidence-based guidelines. Compliance with antimicrobial prophylaxis guidelines were evaluated based on agent and dose. The overall compliance improved from 38.8% pre-intervention to 59.0% post-intervention (p < 0.001). Agent compliance did not improve from pre- to post-intervention, that is, 60.7% to 62.8%, respectively, (p = 0.68), whereas dose compliance improved from 39.6% to 89.2% (p < 0.001). Approximately 78.5% of survey respondents felt that they strongly agreed or agreed with always following evidence-based antimicrobial prophylaxis guidelines. Compliance with antimicrobial prophylaxis guidelines improved, primarily due to increased dosing compliance. Future interventions will target agent compliance and selected procedures with lower compliance rates. 3 Laryngoscope, 133:3403-3408, 2023.

Factors Predicting Compliance with the Uptake of the Third COVID-19 Vaccine among the Arab Minority in Israel

Between December 2020 and February 2021, Israel administered two doses of COVID-19 vaccine to &gt;50% of its adult population. Nonetheless, due to declining immunity and the spread of the COVID-19 delta variant, the government offered a third COVID-19 vaccine dose in July 2021. Although the vaccine was shown to provide effective protection against severe illness, the compliance rate among the Arab minority remained low. The present study sought to identify the factors predicting willingness to uptake the COVID-19 vaccine in the Arab community. An online survey of 2486 participants was conducted in November 2021 to assess vaccination-related behaviours, such as perceived benefits, barriers, incentives (e.g., the green pass), subjective norms, and pandemic fatigue. Positive correlations were found among reasons for obtaining a green pass, trust in formal authorities, perceived effectiveness of the third COVID-19 vaccine dose, subjective norms, and attitudes toward the booster dose. Pandemic fatigue was positively correlated with vaccination barriers. Trust in authorities, perceived booster dose effectiveness, subjective norms, and attitudes were negatively related to pandemic fatigue and barriers to vaccination. Demographic variables such as age, education level, and income level were positively related to odds of getting the booster. Participants who reported being religious exhibited a lower rate of booster dose compliance than secular participants. The study findings show that the reasons for acquiring a green pass were positively correlated with the perceived effectiveness of the booster dose, demonstrating that individuals understood the vaccine benefits. Further, having a green pass was negatively related to barriers. Incentives such as the green pass play a major role in encouraging the population to take the COVID-19 vaccine. In addition, public campaigns to explain the health benefits and refute erroneous myths support higher vaccination rates.

A feasibility, safety, and efficacy evaluation of supervised aerobic and resistance exercise for patients with glioblastoma undertaking adjuvant chemoradiotherapy.

While therapeutically effective, chemoradiotherapy treatment for high-grade glioma (glioblastoma) is often accompanied by side effects. Exercise has been demonstrated to alleviate the adverse effects of such treatments in other cancers. We aimed to evaluate the feasibility and preliminary efficacy of supervised exercise incorporating autoregulation. Thirty glioblastoma patients were recruited, five declined exercise and 25 were provided with a multimodal exercise intervention for the duration of their chemoradiotherapy treatment. Patient recruitment, retention, adherence to training sessions and safety were evaluated throughout the study. Physical function, body composition, fatigue, sleep quality, and quality of life were evaluated before and after the exercise intervention. Eight of the 25 participants commencing exercise withdrew prior to completion of the study (32%). Seventeen patients (68%) demonstrated low to high adherence (33%-100%) and exercise dosage compliance (24%-83%). There were no reported adverse events. Significant improvements were observed for all trained exercises and lower limb muscle strength and function with no significant changes observed for any other physical function, body composition, fatigue, sleep, or quality of life outcomes. Only half of glioblastoma patients recruited were willing or able to commence, complete or meet minimum dose compliance for the exercise intervention during chemoradiotherapy indicating the intervention evaluated may not be feasible for part of this patient cohort. For those who were able to complete the exercise program, supervised, autoregulated, multimodal exercise was safe and significantly improved strength and function and may have prevented deterioration in body composition and quality of life.

How large could the public health impact of introducing recombinant zoster vaccination for people aged ≥50 years in five Latin American countries be?

ABSTRACT This study aimed to: (1) estimate the disease burden of herpes zoster (HZ) and (2) assess the potential public health impact of introducing adjuvanted recombinant zoster vaccine (RZV) compared with no vaccination in adults aged ≥50 years in Argentina, Brazil, Mexico, Chile, and Colombia using the ZOster ecoNomic Analysis (ZONA) static multicohort Markov model. The model followed individuals aged ≥50 years from administration of RZV over their remaining lifetime. Inputs were based, most often, on local data. First dose coverage was assumed to be 35%, with 75% second dose compliance. It was predicted that without RZV, there would be 23,558,675 HZ cases, 6,115,981 post-herpetic neuralgia (PHN) cases, and 7,058,779 non-PHN complications in the five countries, but introducing RZV under assumed coverage could avoid 4,583,787 (19%) HZ cases, 1,130,751 (18%) PHN cases, and 1,373,419 (19%) non-PHN complications. Also, 10427,504 (20%) doctor’s office visits and 1,630,201 (19%) days of hospitalization could be averted in the three countries (Argentina, Brazil, and Mexico) with available input data. The numbers needed to be vaccinated to avoid one case of HZ were 9–10 across countries, and to avoid one case of PHN, 35–40. One-way sensitivity analyses showed that the input parameters with the largest impact on the estimated number of HZ cases avoided were first dose coverage, initial HZ incidence, and vaccine efficacy waning. In conclusion, the introduction of RZV for older adults in Latin America could greatly reduce the public health burden of HZ and reduce the related doctor visits and hospitalization days.

용해도가 개선된 엔잘루타마이드 고체분산체 함유 정제의 개발

The objective of this study was to develop a novel enzalutamide tablet formulation with enhanced solubility and bioavailability, and inhibited recrystallization. Kollidon VA64 was selected as a soluble polymer for preparing enzalutamide solid dispersions. Solid dispersions with different enzalutamide to Kollidon VA64 weight ratios were prepared via solvent evaporation method. The enzalutamide solid dispersion consisting of enzalutamide and Kollidon VA64 at a weight ratio of 1:1, exhibited an excellent dissolution rate and potent inhibition of recrystallization. Enzalutamide solid dispersions were characterized by scanning electron microscopy, powder X-ray diffractometry, differential scanning calorimetry, and in vitro dissolution studies. The 1:1 solid dispersion exhibited excellent productivity, an elevated dissolution rate, and recrystallization inhibition. Therefore, enzalutamide solid dispersion loaded tablets were prepared and their dissolution was evaluated compared to a commercial product (Xtandi® soft capsule). The selected tablet formulation containing enzalutamide solid dispersion exhibited a higher dissolution rate in pH 1.0 solution than did the Xtandi® soft capsule, and prevented recrystallization of the enzalutamide. This research suggests that enzalutamide-containing solid dispersion tablets could be the most effective method to date for improving the dosing compliance of Xtandi® soft capsules, improving the dissolution rate of enzalutamide, and preventing recrystallization.

Modified chitosan nanogel-polymersomes for oral co-delivery of oxaliplatin and rapamycin for synergistic chemotherapy

Oxaliplatin (OXA) and rapamycin (RAPA) combination therapy have shown the advantages of synergistically inhibiting the growth of cancer cells by enhancing apoptosis in cancerous cell lines. However, drug resistance and the lack of an orally administered formulation which exhibited the best clinical dosing compliance limited the clinical application of this regimen. Here, we report a nanogel-polymersomes drug delivery system (i.e.TMOR-CDAN) based on modified chitosan, chitosan diacetate (CDA), methoxy-poly-(ethylene glycol)-b-poly (lactide) (MPP), and D-alpha-tocopheryl polyethylene glycol succinate (TPGS) with permeation-glycoprotein (P-gp) inhibition capability for enhancing the oral chemotherapy efficacy of erroneously soluble RAPA and its synergistic chemotherapy with OXA. Hydrophilic OXA and hydrophobic RAPA were co-loaded using MPP and TPGS-based polymer capsules (i.e. TMOR), which were further coated by chitosan-modified gel to form TMOR-CDAN. The TMOR-CDAN displayed higher stability in both acidic and basic pH than free OXA and RAPA and could withstand the harsh gastric environmental conditions, preventing the burst drugs release while releasing the co-loaded drugs in a sustained and controlled manner. The dual-drug-loaded TMOR-CDAN provides a bifunctional platform for synergistic tumor therapy. Compared with the single drug OXA, RAPA, or the OXA and RAPA mixtures (OR), the TMOR-CDAN showed more outstanding in vitro cytotoxicity and in vivo antitumor chemotherapeutic efficacy, endowing the TMOR-CDAN with a prodigious potential for futuristic cancer chemotherapy.

Stable Recombinant Invasion Plasmid Antigen C (IpaC)-Based Single Dose Nanovaccine for Shigellosis

Shigellosis, caused by the bacteria Shigella, is the leading cause of bacterial diarrhea and the second leading cause of diarrheal death among children under the age of five. Unfortunately, Shigella strains have acquired resistance to antibiotics, and a commercial vaccine is yet to be available. We have previously demonstrated that Shigella dysenteriae serotype 1 (Sd1)-based recombinant, stabilized, "invasion plasmid antigen C" (IpaC; 42 kDa) protein can induce robust immune responses in BALB/c mice against a challenge of a high dose of heterologous Shigella when immunized via three intranasal doses of IpaC without an adjuvant. In this work, in order to reduce the frequency of dosing and increase possible patient compliance, based on our previous screening, the minimum protective dose of stabilized IpaC (20 μg) was encapsulated in biodegradable polymeric poly(lactide-co-glycolide) nanoparticles (∼370 nm) and intranasally administered in BALB/c mice in a single dose. Interestingly, a single intranasal dose of the developed vaccine particles encapsulating only 20 μg of Sd1 IpaC led to a temporal increase in the antibody production with an improved cytokine response compared to free IpaC administered three times as described in our previous report. Upon intraperitoneal challenge with a high dose of heterologous Shigella flexneri 2a (common in circulation), the immunized animals were protected from diarrhea, lethargy, and weight loss with ∼67% survival, while all the control animals died by 36 h of the challenge. Overall, the developed nanovaccine could be explored as a potential noninvasive, cross-protective, single-dose, single-antigen Shigella vaccine amenable for scale-up and eventual mass immunization.

Assessment of an institutional guideline for vancomycin dosing and identification of predictive factors associated with dose and drug trough levels

To evaluate the effectiveness of an antimicrobial guideline for vancomycin prescribing deployed using electronic prescribing aid and web/phone-based app. To define factors associated with guideline compliance and drug levels, and to investigate if antimicrobial dosing recommendations can be refined using routinely collected electronic healthcare record data. We used data from Oxford University Hospitals between 01-January-2016 and 01-June-2021 and multivariable regression models to investigate factors associated with dosing compliance, drug levels and acute kidney injury (AKI). 3767 patients received intravenous vancomycin for ≥24h. Compliance with recommended loading and initial maintenance doses reached 84% and 70% respectively; 72% of subsequent maintenance doses were correctly adjusted. However, only 26% first and 32% subsequent levels reached the target range, and for patients with ongoing vancomycin treatment, 55-63% achieved target levels at 5 days. Drug levels were independently higher in older patients. Incidence of AKI was low (5.7%). Model estimates were used to propose updated age, weight and eGFR specific guidelines. Despite good compliance with guidelines for vancomycin dosing, the proportion of drug levels achieving the target range remained suboptimal. Routinely collected electronic data can be used at scale to inform pharmacokinetic studies and could improve vancomycin dosing.

Novel Esomeprazole Magnesium-Loaded Dual-Release Mini-Tablet Polycap: Formulation, Optimization, Characterization, and In Vivo Evaluation in Beagle Dogs.

Esomeprazole magnesium (EMP) is a proton pump inhibitor (PPI) that reduces acid secretion. EMP has a short plasma half-life (approximately 1.3 h); hence, nocturnal acid breakthrough (NAB) frequently occurs, disturbing the patient’s nighttime comfort and sleep. We aimed to develop a novel esomeprazole magnesium-loaded dual-release mini-tablet polycap (DR polycap) with a prolonged onset time and improved bioavailability to prevent NAB. The formulation of the EPM mini-tablet core resulted in rapid drug release. The core was coated with an inner coating and an Eudragit® L30D-55 aqueous dispersion coating to prepare the first-release mini-tablet. In addition, the core was coated with an inner coating and an aqueous dispersion of Eudragit® S100 and Eudragit® L100 coating to prepare the second-release mini-tablet. Each mini-tablet type was characterized using an in vitro dissolution test and microscopic examination. After testing, 10 of each mini-tablets were placed together in hard capsules to form DR polycaps. The combination of mini-tablets was optimized via in vitro release testing and in vivo pharmacokinetic studies. The AUC0–24h of the DR polycap was similar to that of a comparable commercial product (Nexium®); Cmax was lower by approximately 50%, and Tmax was extended by approximately 1.7-fold. In conclusion, DR polycap is an alternative to commercial products with improved NAB and dosing compliance because of its dual-release characteristics.

Real-World Efficacy and Tolerability of Brigatinib in Patients with Non-Small Cell Lung Cancer with Prior ALK-TKIs in the United States.

BackgroundReal-world evidence for brigatinib, a next-generation anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) used in ALK-rearranged non-small cell lung cancer, is scarce. This retrospective study evaluated real-world brigatinib utilization in the US post other ALK-TKIs.Materials and MethodsAdults with ≥1 brigatinib claim (index date) between 1 April 2017 and 30 September 2020 in the IQVIA longitudinal pharmacy claims database were followed until dose reduction, discontinuation, or end of follow-up. Patients had ≥12 months pre– and ≥1-month post–index observations.ResultsA total of 413 patients treated with brigatinib were analyzed. Over 80% received ≥1 prior ALK-TKI; alectinib and crizotinib were the most common (58.8% and 51.3% patients, respectively). The median follow-up was 8.4 months. The median time to treatment discontinuation (TTD) for brigatinib was 10.3 months (95% CI, 8.2-15.0), with 45% remaining on therapy at 12 months. The TTD was shortest (~8 months) in patients receiving both crizotinib and alectinib and longest in patients who received alectinib only prior to brigatinib (11.8 months). Adherence was high, with 92.7% of patients having a medication possession ratio of >80%. The mean dose compliance score was 1.0. Most patients reached the brigatinib dose of 180 mg/day (77%); 13.2% of patients had a dose reduction, with 89.3% and 84.6% continuing 180 mg/day therapy at 3 and 6 months, respectively.ConclusionsBrigatinib appears to be effective and well-tolerated in the real-world ALK+ NSCLC population in the US, showing benefit in patients after a next-generation ALK-TKI. Notably, dose reduction rates appeared markedly less than those seen in trials when most trial-related dose reductions were for asymptomatic laboratory abnormalities.

Intermodel comparison for the radiological assessment of the Zapadnoe and Tessenderlo case studies with implications for selection of remediation strategy

Risk assessment provides a key input for determining the need for and extent of remedial actions necessary for sites contaminated with naturally occurring radioactive material or nuclear legacy sites. The choice of a modelling approach for risk assessment, and the corresponding toolsets should fit the assessment context, taking account of the complexity, and be clearly related to the questions to be addressed in the decision-making process. One of the objectives of Working Group 1 of IAEA Modelling and Data for Radiological Impact Assessments II (MODARIA II) Programme is to perform intermodel comparisons for case studies of selected sites, in particular, to help illustrate the applicability of different models and approaches as inputs to decision-making processes. This intercomparison exercise, which included the analysis of potential consequences on the management strategy for contaminated sites, has been performed for two sites: The former uranium mill tailings facility at Zapadnoe, Ukraine, and the phosphate processing facility at Tessenderlo, Belgium. Several models and computer codes have been used for one or both of these cases: AMBER, GoldSim, NORM And LegacY Site Assessment, Preliminary Remediation Goals (PRG)-dose compliance concentration calculator, and RESRAD-OFFSITE. The assessments explore the implications of using differing assessment frameworks and assumptions, as well as alternative modelling tools, on model outputs and as input for corresponding decisions on remediation strategy. This paper reviews both similarities and differences in the results of assessments performed using these different models. It discusses how different approaches can complement one another to help build confidence in the evidence base underpinning decisions. It also discusses the appropriateness of the different modelling approaches in a given assessment context. In one of the case studies in particular (Tessenderlo case study), the remediation strategy is essentially driven by the contamination of the site with heavy metals, such as cadmium. This has significant consequences on the choice of the most adequate approaches and scenarios for assessing the radiological risk and balancing their relative importance with other impacts. The development of a holistic approach to risk assessment is, therefore, highlighted.