Dose Of Drug Research Articles

The clinical value of ultrasound-guided sacral anesthesia in Intracavitary and/or interstitial brachytherapy for cervical Cancer

ObjectiveTo explore the effectiveness and safety of ultrasound-guided sacral anesthesia in intracavitary and/or interstitial brachytherapy for cervical cancer patients. MethodA retrospective analysis was conducted on a total of 1039 intracavitary and/or interstitial brachytherapy involving 220 patients in our department from December 7, 2020 to March 21, 2024. The study assessed the satisfaction with anesthesia, changes in vital signs, onset time of anesthesia, dosage of anesthetic drugs, duration of anesthesia, and incidence of adverse reactions. ResultThe rate of satisfaction with anesthesia was 73.8 %. There were no significant differences in patients' heart rate (HR), mean arterial pressure (MAP), systolic blood pressure (SBP), or oxygen saturation (SaO2) before and after anesthesia (P > 0.05). The onset time of anesthesia ranged from 20 to 35 min, the average dosage of anesthetic was 20 ml, and the duration of anesthesia lasted from 30 to 120 min. Serious adverse reactions included 2 cases of post-anesthesia syncope (associated with sacral cysts). The incidence of nausea was 2.2 %, and the total incidence of other adverse reactions, such as vomiting, urinary retention, bradycardia, anal discomfort, and dizziness, was less than 1 %. ConclusionUltrasound guided sacral anesthesia demonstrates significant advantages, including effective anesthesia, minimal impact on vital signs, rapid onset, prolonged maintenance, and a low incidence of adverse reactions. It is recommended for widespread application in intracavitary and/or interstitial brachytherapy for cervical cancer patients.

State of the art of real-life concentration monitoring of rifampicin and its implementation contextualized in resource-limited settings: the Tanzanian case.

The unique medical and socio-economic situation in each country affected by TB creates different epidemiological contexts, thus providing exploitable loopholes for the spread of the disease. Country-specific factors such as comorbidities, health insurance, social stigma or the rigidity of the health system complicate the management of TB and the overall outcome of each patient. First-line TB drugs are administered in a standardized manner, regardless of patient characteristics other than weight. This approach does not consider patient-specific conditions such as HIV infection, diabetes mellitus and malnutrition, which can affect the pharmacokinetics of TB drugs, their overall exposure and response to treatment. Therefore, the 'one-size-fits-all' approach is suboptimal for dealing with the underlying inter-subject variability in the pharmacokinetics of anti-TB drugs, further complicated by the recent increased dosing regimen of rifampicin strategies, calling for a patient-specific methodology. In this context, therapeutic drug monitoring (TDM), which allows personalized drug dosing based on blood drug concentrations, may be a legitimate solution to address treatment failure. This review focuses on rifampicin, a critical anti-TB drug, and examines its suitability for TDM and the socio-economic factors that may influence the implementation of TDM in clinical practice in resource-limited settings, illustrated by Tanzania, thereby contributing to the advancement of personalized TB treatment.

Leveraging Artificial Intelligence for Predictive Healthcare: A Data-Driven Approach to Early Diagnosis and Personalized Treatment

As noted, healthcare delivery systems are systems that always present organizational difficulties for any user and everyone related to these systems, but AI today is one of the widely-discussed and most frequently considered innovations that have prospects for radical improvement of the patient’s state and quality of life. AI solutions are on the verge of becoming integrated into clinical practice thanks to enhanced developments in the field, which means that there is a need to cover the part played by these technologies in healthcare and equip healthcare providers with the knowledge and resources needed to achieve that. This review article provides a broad, although dated, systematic synthesis of AI in clinical practice today, reviewing potential uses of AI in disease taxonomy and diagnosis, treatment suggestions, patient participation, and utilizing methodologies to consider the ethical and legal issues of AI and the persistent need for human insights and expertise. In order to establish the nature of the relationships and possible effects of AI in healthcare environments, the paper reviews the literature using PubMed/Medline, Scopus, and EMBASE databases. According to the findings, the application of AI technologies in health care delivery can greatly improve disease diagnosis, therapy choice, and clinical testing because, in contrast to human decision-making, AI algorithms analyze extensive data sets and outcompete human experts in specific tasks. It is accurate, cost-effective, time efficient, and free from human errors, advances the fields of pharmacogenomics and personalized medicine, optimizes the dosing of drugs, improves overall population health, establishes virtual healthcare services, and enhances mental health care, education, and trust between patients and physicians. Nevertheless, these and the following issues cannot be left unresolved: data privacy, AI bias, and the indispensability of the human factor.

Long-Term Efficacy and Safety of Risankizumab for Active Psoriatic Arthritis: 196-Week Results From the KEEPsAKE 2 Trial

Introduction & Objectives: Here, we report the long-term efficacy and safety of risankizumab (RZB) in patients with active psoriatic arthritis (PsA) through week 196 of the KEEPsAKE 2 trial. Materials & Methods: Adult patients with previous inadequate response or intolerance to 1 or 2 biological therapies (Bio-IR) and/or ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR) were randomized in a 1:1 ratio to subcutaneous RZB 150mg or matched placebo for a 24-week double-blind placebo controlled period. Starting at week 28, patients received open-label RZB every 12 weeks thereafter. Efficacy and safety analyses were conducted in all randomized patients who received ≥1 dose of the study drug. Statistical approaches included non-responder imputation incorporating multiple imputation (NRI-MI) for binary endpoints, and mixed-effect model for repeated measures (MMRM) for categorical endpoints at week 196. Safety assessments based on treatment emergent adverse events (TEAEs) are summarized using exposure-adjusted event rates (EAERs, events/100 patient-years [E/100PYs]). Results: 51.3% of patients on RZB 150mg (N=224) achieved the primary endpoint of ACR20 at week 24 compared to 26.5% on placebo (N=219). Patients on open-label RZB maintained similar efficacy results at week 196 as those reported previously at weeks 24, 52, 100, and 148. At week 196, 54.5% patients receiving continuous RZB and 50.2% patients on PBO/RZB achieved ACR20; 35.3% on RZB and 37.0% on PBO/RZB achieved ACR50; 35.3% on RZB and 37.4% on PBO/RZB achieved minimal disease activity (MDA). In patients with psoriasis severity of ≥ 3% of body surface area (BSA) at baseline, 66.7% on RZB and 56.3% on PBO/RZB achieved PASI90 at week 196. In patients with enthesitis at baseline, 49.0% on RZB and 50.0% on PBO/RZB achieved resolution. In patients with dactylitis at baseline, 75.0% on RZB and 59.6% on PBO/RZB achieved resolution. Among patients with HAQ-DI scores of at least 0.35 at baseline, 36.7% on RZB and 40.6% on PBO/RZB achieved improvements of at least 0.35 at week 196. The overall rates of TEAEs (170.7 E/100PYs), serious TEAEs (9.8 E/100PYs) and AEs leading to discontinuation of study drug (1.4 E/100PYs) remained stable and consistent with rates reported previously at week 24 for the placebo-controlled period, and weeks 52, 100, and 148. Conclusion: The 196-week results from KEEPsAKE 2 demonstrate that long-term treatment with RZB shows durable efficacy in Bio-IR and/or csDMARD-IR patients with PsA, with no new safety findings.

Long-Term Efficacy and Safety of Risankizumab for csDMARD-IR Patients With Active Psoriatic Arthritis: 196-Week Results From the KEEPsAKE 1 Trial

Introduction & Objectives: Here, we report the long-term efficacy and safety of risankizumab (RZB) in patients with active psoriatic arthritis (PsA) through week 196 from the KEEPsAKE 1 trial. Materials & Methods: The ongoing KEEPsAKE 1 clinical trial is a global, phase 3, multicenter study to evaluate the efficacy and safety of RZB versus placebo (PBO) in patients with active PsA. Patients are at least 18 years old and demonstrated an inadequate response, intolerance or contraindication to ≥1 conventional synthetic disease modifying antirheumatic drug (csDMARD-IR). Following a 24-week double-blind, PBO-controlled, parallel-group treatment period (period 1), all patients received open-label RZB every 12 weeks thereafter (period 2). Safety assessments were based on monitoring of treatment-emergent adverse events (TEAEs) reported as events per 100 patient-years (PY). Efficacy and safety analyses were conducted in all randomized patients who received ≥1 dose of the study drug. Results: Overall efficacy results were maintained at week 196 of the KEEPsAKE 1 trial, as compared to previously reported timepoints. At week 196, 39.4% of patients receiving continuous RZB and 38.1% of PBO/RZB patients achieved ACR50; 39.6% of RZB and 35.2% of PBO/RZB patients achieved MDA. In patients with psoriasis severity of ≥ 3% of body surface area (BSA) at baseline, 65.2% on RZB and 62.9% on PBO/RZB achieved PASI90 at week 196. mNAPSI and PGA-F scores improved from baseline by 14.99 and 1.5 points, respectively, for RZB, and by 14.73 and 1.5 points for PBO/RZB patients. In patients with enthesitis at baseline, 60.1% on RZB and 63.4% on PBO/RZB achieved resolution. For patients with dactylitis at baseline, 72.3% on RZB and 77.6% on PBO/RZB achieved resolution. HAQ-DI (RZB -0.40, PBO/RZB -0.33), SF-36 PCS (RZB 8.98, PBO/RZB 7.21) and FACIT-Fatigue (RZB 7.7, PBO/RZB 5.6) scores maintained improvement from baseline to week 196. The overall rates of TEAEs (121.4 E/100PY), serious TEAEs (7.7 E/100PY) and AEs leading to discontinuation of study drug (1.8 E/100PY) have remained stable and comparable to those reported in period 1. Conclusion: The 196-week results of the ongoing KEEPsAKE 1 trial demonstrate the durable efficacy of RZB 150 mg in treating the different clinical manifestations and improving health-related quality of life in csDMARD-IR patients with PsA. RZB continued to be well-tolerated, with no new safety signals.

Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial

Abstract Objectives To assess the efficacy and safety of the non-hormonal, neurokinin 3 receptor antagonist, fezolinetant, to treat moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy. Design Phase 3b randomised controlled trial. Setting 16 countries. Participants 453 individuals aged 40-65 years with moderate-severe vasomotor symptoms associated with menopause who were considered unsuitable candidates for hormone therapy (contraindicated, caution (based on medical history), stoppers (previous discontinuation of hormone therapy), or averse (informed choice not to use hormone therapy)) were randomised to receive fezolinetant (n=227) or placebo (n=226). Intervention Fezolinetant 45 mg or placebo once daily for 24 weeks. Main outcome measures The primary endpoint was mean change in daily frequency of moderate-severe vasomotor symptoms from baseline to week 24. Secondary endpoints were mean change in symptom severity, sleep disturbance using the Patient-Reported Outcome Measurement Information System Sleep Disturbance Short Form (PROMIS SD-SF) 8b total score, and safety. Results 370 (81.7%) participants completed the study (fezolinetant=195, placebo group=175). The safety and full analysis sets comprised 452 participants who received at least one dose of study drug. Mean age was 54.5 (standard deviation 4.7) years and most of the participants (435 (96.7%) were white and categorised as either hormone therapy averse (168 (37.2%)) or caution (165 (36.5%)). At week 24, fezolinetant significantly reduced the frequency (least squares mean difference –1.93, 95% confidence interval (CI) –2.64 to –1.22; P<0.001) and severity of vasomotor symptoms (–0.39, –0.57 to –0.21; P<0.001). At week 24, the fezolinetant group had a greater reduction in sleep disturbance (PROMIS SD-SF 8b total score) compared with placebo (–2.5, –3.9 to –1.1; P<0.001). Improvements over placebo were observed as early as week 1. Both groups showed similar incidences of treatment emergent adverse events (TEAEs, 147 (65.0%) in the fezolinetant group, 138 (61.1%) in the placebo group) and serious TEAEs (10 (4.4%) and 8 (3.5%), respectively). The most common TEAEs in the fezolinetant group were covid-19 (30 (13.3%)), headache (20 (8.8%)), and fatigue (13 (5.8%)). Conclusions Fezolinetant was efficacious and well tolerated over a six month period for treating moderate-severe vasomotor symptoms in individuals considered unsuitable for hormone therapy. These results highlight the utility of fezolinetant as an effective treatment option for those who have contraindications to or choose not to use hormone therapy. Trial registration ClinicalTrials.gov NCT05033886 ; EudraCT 2021-001685-38.

Precision Medicine Proof-of-Concept Study of a TNF Inhibitor in FSGS and Treatment-Resistant Minimal Change Disease

Background: Focal segmental glomerulosclerosis (FSGS) and treatment-resistant minimal change disease (TR-MCD) are heterogeneous disorders with subgroups defined by distinct underlying mechanisms of glomerular and tubulointerstitial injury. A non-invasive urinary biomarker profile has been generated to identify patients with intra-kidney tumor necrosis factor (TNF)-activation and to predict response to anti-TNF treatment. We conducted this proof-of-concept, multi-center, open-label clinical trial to test the hypothesis that in patients with FSGS or TR-MCD and evidence of intra-renal TNF activation based on their biomarker profile, short-term treatment with adalimumab would reverse the elevated urinary excretion of MCP-1 and TIMP-1. Methods: Patients with FSGS or TR-MCD, eGFR>30 ml/min/1.73 m2, urine protein:creatinine ratio (UPCR) ≥1.5 g/g, and age 6-80 year were eligible for this trial. Adalimumab, 20-40 mg, was administered via subcutaneous injection, every 2 weeks for 5 doses. Participants were evaluated at weeks 0 (Baseline), 2, 8, and 10. Excretion of urinary (u) uMCP-1, uTIMP-1, uEGF, and plasma MCP-1 were measured at each visit. Results: Seven participants were enrolled, with median baseline UPCR 12.1 mg/mg (IQR: 2.2, 18.6), serum albumin 2.4 g/dL (IQR: 2.0, 2.8), and eGFR 57 mL/min/1.73 m2 (IQR: 44, 96). Based on self-report, they received all prescribed doses of adalimumab. The patients with the most favorable response based on the changes in urinary biomarkers had the best preserved kidney parenchyma based on uEGF excretion. Conclusions: Precision medicine trials are feasible in rare glomerular disorders. In this pilot study, adalimumab resulted in a heterogenous response of the candidate mechanistic-predictive biomarkers of TNF-mediated inflammation in patients with FSGS or TR-MCD. A reduction was seen in a subgroup of patients with preserved kidney parenchyma. The findings may reflect the challenge to reverse chronic injury at advanced stages of kidney disease or insufficient intra-renal target engagement with the intervention drug dose.

The Efficacy of Combined “Oral Simvastatin Plus Narrowband UVB Phototherapy” Than “Phototherapy Alone” in Treating Skin Lesions in Patients with Vitiligo, a Double-Blind Add-On Randomized Controlled Clinical Trial

Background: A tailored therapy for vitiligo is crucial in enhancing patients' quality of life and decreasing the associated dimensions. In addition, statins play a significant function in modulating the immune system. Objectives: This study investigated the efficacy of oral simvastatin in treating skin lesions in patients with vitiligo. Methods: This interventional randomized clinical trial enrolled 50 vitiligo patients referred to Shahid Faghihi Hospital in Shiraz (Iran) in 2015. Participants were divided into control and intervention groups using block randomization. Participants in the control group received “NB-UVB phototherapy plus placebo,” and those in the intervention group received “NB-UVB phototherapy with 40, 60, and 80 mg simvastatin by a monthly increase in the drug dosage”. A reduction in the Vitiligo Area Scoring Index (VASI) score and side effects were measured for four months, and the results were compared between the two groups. Results: At the start of the study, the mean score for the disease severity was equal for both groups (P ˃ 0.05). However, the disease severity was significantly reduced in the following stages of the study in the simvastatin group compared to the placebo group (P = 0.0001). Conclusions: Oral simvastatin enhances the photothermal outcomes while exerting trivial side effects. Thus, combining oral simvastatin with phototherapy is recommended as a potent strategy for treating patients with vitiligo.

A cascade X-ray energy converting approach toward radio-afterglow cancer theranostics.

Leveraging X-rays to initiate prolonged luminescence (radio-afterglow) and stimulate radiodynamic 1O2 production from optical agents provides opportunities for diagnosis and therapy at tissue depths inaccessible to light. However, X-ray-responsive organic luminescent materials are rare due to their intrinsic low X-ray conversion efficiency. Here we report a cascade X-ray energy converting approach to develop organic radio-afterglow nanoprobes (RANPs) for cancer theranostics. RANPs comprise a radiowave absorber that down-converts X-ray energy to emit radioluminescence, which is transferred to a radiosensitizer to produce singlet oxygen (1O2). 1O2 then reacts with a radio-afterglow substrate to generate an active intermediate that simultaneously decomposes to emit radio-afterglow. Through finetuning such a cascade, intraparticle radioluminescence energy transfer and the 1O2 transfer process, RANPs possess tunable wavelengths and long half-lives, and generate radio-afterglow and 1O2 at tissue depths of up to 15 cm. Moreover, we developed a biomarker-activatable nanoprobe (tRANP) that produces a tumour-specific radio-afterglow signal, leading to ultrasensitive detection and the possibility of surgical removal of diminutive tumours (1 mm3) under an X-ray dosage 20 times lower than inorganic materials. The efficient radiodynamic 1O2 generation of tRANP permits complete tumour eradication at an X-ray dosage lower than clinical radiotherapy and a drug dosage one to two orders of magnitude lower than most existing inorganic agents, leading to prolonged survival rates with minimized radiation-related adverse effects. Thus, our work reveals a generic approach to address the lack of organic radiotheranostic materials and provides molecular design towards precision cancer radiotherapy.

Application of mathematical models in predicting drug dosage and its efficacy

The purpose of the research is to form a comprehensive understanding of how mathematical models are used to interpret complex dynamics related to the distribution, metabolism and excretion of drugs in the human body. The use of mathematical models to predict the required dose of drug prescriptions and establish its effectiveness means a paradigm shift in the field of pharmacology.Methods. The methodology used in this study was aimed at identifying and analytically reviewing articles that correspond to the objectives of the study. The publications included in the analysis were analyzed and data extracted, focusing on key information such as the mathematical modeling methodology used, the exact predicted treatment effects, the populations studied, long-term prognostic effects, and the assessment of the use of various drug dosing regimens.Results. In total, 12 publications were analyzed, which used four different methodologies: models with the effects of several different conditions, models that take into account the occurrence of various discrete events, models based on the effects of informative signs taking into account the physiology of individuals, as well as survival models and generalized linear models.Conclusion. The conducted study of the current state of mathematical modeling in medical research for the purpose of comparative effectiveness is intended for practicing scientists and doctors in conducting further research and introducing innovations. Despite the challenges, the potential impact of these models aimed at bridging the gap between the controlled clinical environment and the real health context is undeniable. The use of mathematical modeling methods to predict the dosage of medicines will improve the quality and effectiveness of personalized medical appointments in the coming years.

Tetrandrine induces muscle atrophy involving ROS-mediated inhibition of Akt and FoxO3.

Tetrandrine (Tet), a well-known drug of calcium channel blocker, has been broadly applied for anti-inflammatory and anti-fibrogenetic therapy. However, due to the functional diversity of ubiquitous calcium channels, potential side-effects may be expected. Our previous report revealed an inhibitory effect of Tet on myogenesis of skeletal muscle. Here, we found that Tet induced protein degradation resulting in the myofibril atrophy. Upon administration with a relative high dose (40mg/kg) of Tet for 28days, the mice displayed significantly reduced muscle mass, strength force, and myosin heavy chain (MyHC) protein levels. The MyHC reduction was further detected in C2C12 myotubes after treating with Tet. Interestingly, the expression of Atrogin-1 and Murf-1, the skeletal muscle specific E3 ligases of protein ubiquitin-proteasome system (UPS), was accordingly up-regulated, and the reduced MyHC was significantly mitigated by MG132, a 26S proteasome inhibitor, indicating a key role of UPS in the protein degradation of muscle cells. Further study showed that Tet induced autophagy also participated in the protein degradation. Mechanistically, Tet treatment caused ROS production in myotubes that in turn targeted on FoxO3/AKT signaling, resulting in the activation of UPS and autophagy processes that were involved in the protein degradation. Our study reveals a potential side-effect of Tet on skeletal muscle atrophy, particularly when the drug dose is relatively high.

Efficacy and safety of remimazolam tosylate for patients undergoing off-pump coronary artery bypass grafting: a study protocol for a non-inferiority randomised controlled trial in China

IntroductionMaintaining haemodynamic stability is crucial but challenging during the induction and maintenance of general anaesthesia (GA) in patients undergoing off-pump coronary artery bypass grafting (OPCABG). Remimazolam tosylate is a novel...

Dental dysplasia in childhood cancer survivors: a case series of permanent tooth abnormalities.

This study was performed to investigate the association of dental dysplasia with childhood cancer. We examined the occurrence of agenesis, microdontia, and enamel changes of permanent teeth in pediatric cancer survivors. Seventy-six patients with pediatric cancer and hematologic diseases were referred to our department for the first time from October 2005 to December 2019. Of these, 17 patients who presented for a checkup in our department fulfilled the study criteria and were analyzed. Clinical examinations and panoramic radiographs were performed to investigate dental dysplasia of permanent teeth. A total of 34 developmental abnormalities (18 missing teeth, 16 cases of microdontia) occurred in 5 patients. The patients' medical records were also analyzed to assess the relationships of specific types of dysplasia with the treatment duration and cumulative drug dose administered. All five pediatric cancer survivors had dental dysplasia; all five had tooth agenesis, and four had microdontia. All five patients were < 4 years of age and had undergone high-dose chemotherapy. In this study, childhood cancer survivors who received high-dose chemotherapy before age 4 years experienced the dental dysplasia, including tooth agenesis, microdontia. These findings highlight the need for careful dental monitoring and early intervention in pediatric patients undergoing high-dose chemotherapy. This research was conducted in accordance with the Declaration of Helsinki and approved by the Medical Ethics Committee of the Medical University of Kobe (protocol code No. B230066, 1 September 2023).

Perspectives, Experiences, and Practices of Healthcare Professionals and Patients Towards Herb-Drug Interaction: A Systematic Review of Qualitative Studies.

The aim of the study was to understand healthcare professionals, pharmacists, and patients perspectives and experiences on clinical practice of herb-drug interactions (HDIs). A systematic review of qualitative studies was conduct. 10 electronic databases were searched from inception through September 2023. Qualitative studies, mixed-method studies, and unstructured or semi-structured cross-sectional surveys focused on healthcare professionals, pharmacists and patients' perspectives, attitudes, clinical practice behaviors, and information needs regarding HDI were included. Thematic synthesis employed Nvivo 12 software. Of 6655 studies identified, 1267 full-text articles were retrieved. Of these, 18 studies conducted in 11 countries/regions were eligible for inclusion, involving 1273 patients, 302 healthcare professionals, and 230 pharmacists. Five over-arching explanatory themes were identified: perspectives, attitudes, practices, experiences, expectations, and information needs. Complementary and alternative (CAM) physicians, pharmacists, and general practitioners were considered by patients to possess the ability or responsibility to assess potential HDIs. Pharmacists yet encountered difficulties due to conflicting information sources and inadequate training. Healthcare professionals, including pharmacists, usually only assessed HDIs when they were deemed to cause serious adverse effects. Regarding expectations and information needs, patients were particularly concerned about the risk of adverse HDIs, the severity of HDIs, and the appropriate intervals between drug doses. They would like to receive relevant HDI alerts. Results suggest that government, policy makers, healthcare professionals, and the education system should give attention to HDIs and improve health professional-patient communication. Further research should also be conducted on the understanding and practices of CAM practitioners in China. Trial Registration: CRD42022324777 (https://www.crd.york.ac.uk/PROSPERO/#recordDetails).

Introduction to Instruments used in Pharmacology with its Application

Pharmacology is a multidisciplinary field that focuses on the study of drug interactions, mechanisms of action, and therapeutic effects. The advancement of pharmacological research and clinical applications is heavily dependent on various specialized instruments that enable precise measurement, analysis, and monitoring of drug properties and their effects on biological systems. Instruments used in pharmacology range from simple laboratory tools, such as spectrophotometers and chromatographs, to more complex systems like high chromatography (HPLC), mass spectrometry (MS), and in vivo imaging devices. These tools are essential for drug discovery, pharmacokinetic studies, dose assessments, and toxicological evaluations. The development and application of these instruments allow researchers to accurately quantify drug concentrations, monitor physiological changes, and identify potential drug targets, thereby facilitating the discovery of safe and effective pharmaceutical agents. This introduction provides an overview of the fundamental instruments commonly used in pharmacology and highlights their critical roles in modern drug development and research..

The Use of Slack Variables in the Adjoint Method Handling Inequality Constraints in Optimal Control and the Application to Tumor Drug Dosage

Abstract In this article a modified gradient approach, based on the adjoint method, is introduced, to deal with optimal control problems involving inequality constraints. So far, the only way to incorporate inequality constraints in the adjoint approach, is to introduce additional penalty terms in the cost functional. However, this may distort the optimal control due to weighting factors required for these terms and raise serious concerns about the magnitude of the weighting factors. The method in this article avoids penalty functions and can be used for the iterative computation of optimal controls. In order to demonstrate the key idea, first, a static optimization problem in the Euclidean space is considered. Second, the presented approach is applied to the tumor anti-angiogenesis optimal control problem in medicine, which addresses an innovative cancer treatment approach that aims to inhibit the formation of the tumor blood supply. The tumor anti-angiogenesis optimal control problem with free final time involves inequality and final constraints for control and state variables and is solved by a modified adjoint gradient method introducing slack variables. It has to be emphasized that the novel formulation and the special use of slack variables in this article delivers high accurate solutions without distorting the optimal control.

The Potential of Plant Polysaccharides and Chemotherapeutic Drug Combinations in the Suppression of Breast Cancer

Breast cancer is the most common cancer affecting women worldwide. The associated morbidity and mortality have been on the increase while available therapies for its treatment have not been totally effective. The most common treatment, chemotherapy, sometimes has dangerous side effects because of non-specific targeting, in addition to poor therapeutic indices, and high dose requirements. Consequently, agents with anticancer effects are being sought that can reduce the side effects induced by chemotherapy while increasing its cytotoxicity to cancer cells. This is possible using natural compounds that are safe and biologically active. There are many reports on plant polysaccharides due to their bioactive and anticancer properties. The use of plant polysaccharide together with a conventional cytotoxic drug may offer wide benefits in cancer therapy, producing synergistic effects, thereby reducing drug dose and, so, its associated side effects. In this review, we highlight an overview of the use of plant polysaccharides and chemotherapeutic drugs in breast cancer preclinical studies, including their mechanisms of anticancer activities. The findings emphasize the potential of plant polysaccharides to improve chemotherapeutic outcomes in breast cancer, paving the way for more effective and safer treatment strategies.

A Systematic Review of the Costs of Drug-Associated Acute Kidney Injury and Potential Cost Savings with Nephrotoxin Stewardship Prevention Strategies.

There is a scarcity of information related to the financial impact of acute kidney injury (AKI), and even more so the economics of drug-associated AKI (D-AKI). Our goal was to provide a comprehensive summary of the economic burden of D-AKI by evaluating the costs of D-AKI compared to not developing AKI and cost savings associated with nephrotoxin stewardship approaches. Following the PRISMA guidelines, a literature search was conducted using PubMed to identify articles from database inception through November 2023. The main outcomes included AKI incidence, resource use, and cost of nephrotoxin stewardship programs/D-AKI event or no event. Key findings were summarized based on whether the study compared the cost of D-AKI vs. no AKI or identified potential cost savings associated with a nephrotoxin stewardship method to prevent D-AKI or worsening D-AKI. All costs were adjusted to USD2023. Twenty-five studies met the inclusion criteria. Eight studies compared the cost of D-AKI to no AKI. Total admission costs of patients who developed D-AKI ranged from $47,696 to $173,569. Nineteen studies implemented nephrotoxin stewardship with 12 substituting a less nephrotoxic drug; five using therapeutic drug monitoring and two altering drug dosing to limit exposure. Overall, these prevention strategies ranged from $5,171 to $364,973 in total medical cost savings and $17 to $942 in total cost savings per patient-day. The in-hospital economic impact of D-AKI is substantial. Implementing nephrotoxin stewardship strategies to reduce D-AKI is associated with cost savings. Institutions should adopt strategic and efficient nephrotoxin stewardship programs to optimize patient care and reduce costs.

Assessing Drug Sensitivity in Fission Yeast Using Half-Maximal Inhibitory Concentration (IC50) Assays.

Fission yeast is an excellent model organism in which to study mammalian drug sensitivities. In addition to building a mechanistic picture of drug effect, fission yeast screens may be valuable in determining compounds that show synthetic lethality effects. While compounds might be screened for a variety of phenotypes, an effective method is to detect the proliferative effects of a new compound on a yeast culture. This is traditionally performed in acute viability assays or spot tests; both methods require some knowledge of concentration to observe an effect. Mammalian cell culture experiments that assess proliferation to indicate drug dose and effect are well described. However, differences between S. pombe growth characteristics and mammalian cells mean that importing a mammalian viability assay requires consideration of potential effects on fission yeast biology. We describe the half-maximum inhibitory (IC50) dose as a method of rapid proliferation effect screening. IC50 determination is performed on liquid cultures in 96-well plates and may be developed for initial compound library uses or in synthetic lethality screening of drug effects.

Effect of Esophageal Dilation History on Efficacy Outcomes in Patients With Eosinophilic Esophagitis Receiving Budesonide Oral Suspension

INTRODUCTION: The effect of esophageal dilation history on efficacy outcomes in patients with eosinophilic esophagitis (EoE) receiving swallowed corticosteroids is not well established. METHODS: This post hoc analysis assessed data from a 12-week, randomized, double-blind, placebo-controlled phase 3 study (NCT02605837) of budesonide oral suspension (BOS) 2.0 mg twice daily in patients aged 11–55 years with EoE and dysphagia. Co-primary efficacy outcomes were histologic (≤6 eosinophils per high-power field [eos/hpf]) and dysphagia symptom (≥30% reduction in Dysphagia Symptom Questionnaire [DSQ] scores from baseline) responses at week 12. Secondary efficacy outcomes included histologic response (&lt;15 eos/hpf) and change from baseline to week 12 in DSQ scores and EoE Endoscopic Reference Scores (EREFS). Data were analyzed post hoc by esophageal dilation history (dilation history vs no dilation history). RESULTS: Of 318 patients who received ≥1 dose of study drug, 42.8% had a history of esophageal dilation (dilation history: BOS, n=91; placebo, n=45; no dilation history: BOS, n=122; placebo, n=60). Histologic responses (≤6 and &lt;15 eos/hpf) were similar regardless of dilation history. Fewer BOS-treated patients with dilation history than no dilation history achieved a dysphagia symptom response (44.0% vs 59.0%); conversely a slightly greater improvement from baseline in total EREFS was observed for BOS-treated patients with dilation history than no dilation history (LS mean [standard error of the mean]: −4.1 [0.3] vs −3.4 [0.4]). CONCLUSIONS: Esophageal dilation history may confound the association between histologic outcomes and dysphagia symptom or endoscopic efficacy outcomes in patients with EoE receiving swallowed corticosteroids.