Dose Optimisation Studies Research Articles

Therapeutic potential of Aloe vera-coated curcumin encapsulated nanoparticles in an Alzheimer-induced mice model: behavioural, biochemical and histopathological evidence

Objective The main purpose of the present study was to evaluate the therapeutic efficacy of Aloe vera-coated curcumin encapsulated nanoparticles in mitigating Alzheimer’s disease progression in mice, by examining behavioural changes, biochemical markers, and histopathological alterations, thus elucidating its potential as a treatment strategy. Methods The green synthesis method was used to synthesise this nanoformulation, which was then characterised using a variety of techniques, including percentage encapsulation efficacy, UV-visible spectroscopy, DLS, FT-IR, FESEM, and EDX. Several in-vivo assessments, including behavioural evaluations, dose optimisation studies, oxidative stress marker estimation, and histological studies, were conducted to determine the potential therapeutic impact of nanoformulation on the Alzheimer-induced mice model. Results The synthesised nanoparticles show a mean diameter of 76.12 nm ±1.23, a PDI of 0.313 ± 0.02, a zeta potential of 6.27 ± 0.65 mV, and the percentage encapsulation efficiency between 90% and 95% indicating good stability of synthesised nanoformulation. With the help of Morris water maze, Y-maze, and novel object recognition assay, the learning capacity and memory were assessed, and the results show that the synthesised nanoformulation significantly decreased the transfer latency to reach baited arm or to the hidden platform within 7 days. Conclusion The formulation demonstrated significant biochemical benefits and remarkable cognitive advantages, establishing it as a prospective therapeutic intervention option that is both safe and effective.

Efficacy and Safety of Mavacamten in the Treatment of Hypertrophic Cardiomyopathy: A Systematic Review.

Current pharmacological options for hypertrophic cardiomyopathy (HCM) are not disease-specific; while it treats symptoms, mavacamten targets the underlying pathology. We aim to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive HCM. This systematic review of the literature followed the PRISMA guidelines. Title/abstract and topics were searched using the following term: "mavacamten". The electronic research literature databases included the Cochrane Library, MedLine, and clinicaltrials.gov from July to August 2022. Primary efficacy endpoint was to assess clinical response at the end of treatment compared with baseline, defined as, at least one New York Heart Association (NYHA) class reduction. Two secondary endpoints from baseline were determined. The first was defined as improvement in mixed venous oxygen pressure (pVO2). The second was defined as reduction of the post-exercise left ventricular outflow tract (LVOT) gradient. We included in our analyses data from four studies that met our review eligibility criteria. There were three randomised placebo-controlled clinical trials and one non-randomised open-label clinical trial. All four studies showed a reduction in NYHA class from mavacamten use. Three out of four studies demonstrated >1 NYHA functional class improvement ranging from 34% to 80%, while only one study showed a smaller percentage of patients remaining at class 3. Three out of four studies measured pVO2 as an outcome, and all three studies noticed an increase in peak oxygen consumption after mavacamten treatment. Additionally, three out of four studies measured post-exercise LVOT gradient reduction as an outcome and all three found significant reduction in the post-exercise LVOT gradient after treatment. The most commonly observed adverse side effects were atrial fibrillation and decreased left ventricular ejection fraction, but all participants recovered without long-term sequelae and only one patient dropped out of the trial. Mavacamten has a greater efficacy than placebo in the treatment of HCM. It also showed promising tolerability and efficacy profiles in the treatment of HCM in adults. The three endpoints used in the evaluation of studies were reduction in NYHA class, increase in pVO2, and post-exercise LVOT gradient reduction. Mavacamten showed greater reduction in NYHA, larger effects on increase of pVO2, and significant reduction of the LVOT gradient. Mavacamten was also found to be well tolerated, like the placebo. The side effect profile was limited for the majority of individuals taking mavacamten. In the future, authors recommended dose-optimisation studies, and studies that evaluate mavacamten both in comparison to, and in conjunction with other current treatments.

Low-cost chest paediatric phantom for dose optimisation: construction and validation

Introduction and objectivesIn order to perform chest dose optimisation studies, the imaging phantom should be adequate for image quality evaluation. Since high-end phantoms are cost prohibitive, there is a need for a low-cost construction method with fairly available tissue substitutes. Materials and methodsTheoretical calculations of radiological characteristics were performed for each of lung, cortical bone and soft tissues in order to choose appropriate substitute, then, cork, P.V.C. (Polyvinyl chloride) and water were chosen, respectively. Validation included, firstly, measuring CT Hounsfield Units (HU) of a real patient’s tissues then compared against their corresponding anatomies in the constructed phantom. Secondly, Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) values were acquired in this study to evaluate the quality of images generated from the constructed phantom, then, compare their trends with a valid phantom under different exposure parameters (kVp and mAs). ResultsFrom theoretical calculations, the percentage differences showed high accuracy of tissue substitutes when simulating real patient tissues; P.V.C. was ≥5.78%, cork was ≥4.46% and water ≥5%. The percentage difference (CT HU) between lung and cortical bone and their equivalent tissue substitutes were 10.44% and 0.53%–3.17%, respectively. Strong positive correlations were found for SNR when changing both kVp (0.79) and mAs (0.65). While the correlation strength of CNR values were found to be moderate when changing both kVp (0.58) and mAs (0.53). ConclusionsOur low-cost phantom approved through CT HU that their materials replicate the radiological characteristics of real one-year-old child while SNR and SNR correlations confirmed its applicability in imaging and optimisation studies.

Project Optimus, an FDA initiative: Considerations for cancer drug development internationally, from an academic perspective.

Modern cancer therapeutics are increasingly targeted, bringing the promise of new and improved activity, alongside better tolerability. However, while many are indeed resulting in dramatic improvements in disease control and patient survival, short- and long-term tolerability has not always accompanied it. The choice of dose and schedule is often in the upper range of the therapeutic window, driven by the maximum tolerated dose (MTD) model of previous cytotoxic agents. There is increasing recognition that this needs to change, by taking a more holistic approach to determine the optimal dose for desired biological effects and tolerability early in clinical development. In the US, the FDA's Oncology Centre of Excellence is addressing this via the Project Optimus initiative: aiming to reform dose optimisation studies so that they can demonstrate the most appropriate dose selection. Early clinical development will need to demonstrate the dose-exposure, -pharmacodynamic, -toxicity and -activity relationships, including randomised evaluations for dose selection. Regulatory agencies outside the US are similarly exploring this. Along with Australia, Brazil, Canada, Israel, Singapore and Switzerland, the UK participates in Project Orbis, a collaborative program with the FDA to accelerate patient access to new cancer medicines through coordinated regulatory review. Close alignment with Project Optimus will be important internationally and will require changes across industry, including for academic units and small biotech. We discuss our perspective on the implications, and opportunities, for early phase oncology trials as a uniquely charity-funded drug development facility, the Centre for Drug Development within the Cancer Research UK charity.

Construcción y validación de un fantoma torácico pediátrico asequible para optimizar la dosis

Introduction and ObjectivesIn order to perform chest dose optimisation studies, the imaging phantom should be adequate for image quality evaluation. Since high-end phantoms are cost prohibitive, there is a need for a low-cost construction method with fairly available tissue substitutes. Materials and MethodsTheoretical calculations of radiological characteristics were performed for each of lung, cortical bone and soft tissues in order to choose appropriate substitute, then, cork, P.V.C. (Polyvinyl Chloride) and water were chosen, respectively. Validation included, firstly, measuring CT Hounsfield Units (HU) of a real patient's tissues then compared against their corresponding anatomies in the constructed phantom. Secondly, Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) values were acquired in this study to evaluate the quality of images generated from the constructed phantom, then, compare their trends with a valid phantom under different exposure parameters (kVp and mAs). ResultsFrom theoretical calculations, the percentage differences showed high accuracy of tissue substitutes when simulating real patient tissues; P.V.C. was ≥ 5.78%, cork was ≥ 4.46% and water ≥ 5%. The percentage difference (CT HU) between lung and cortical bone and their equivalent tissue substitutes were 10.44% and 0.53%-3.17%, respectively. Strong positive correlations were found for SNR when changing both kVp (0.79) and mAs (0.65). While the correlation strength of CNR values were found to be moderate when changing both kVp (0.58) and mAs (0.53). ConclusionsOur low-cost phantom approved through CT HU that their materials replicate the radiological characteristics of real one-year-old child while SNR and SNR correlations confirmed its applicability in imaging and optimisation studies.

Impact of acquisition parameters on dose and image quality optimisation in paediatric pelvis radiography—A phantom study

PurposeWithin paediatric pelvis imaging there is a lack of systematic dose optimisation studies which consider age and size variations. This paper presents data from dose optimisation studies using digital radiography and pelvis phantoms representing 1 and 5-year-old children. Material and methodDose optimisation included assessments of image quality and radiation dose. Systematic variations using a factorial design for acquisition factors (kVp, mAs, source-detector distance [SDD] and filtration) were undertaken to acquire AP pelvis X-ray images. Perceptual image quality was assessed using a relative and absolute visual grading assessment (VGA) method. Radiation doses were measured by placing a dosimeter at the radiographic centring point on the surface of each phantom. Statistical analyses for determining the optimised parameters included main effects analysis. ResultsOptimised techniques, with diagnostically acceptable image quality, for each paediatric age were: 1-year-old; 65 kVp, 2 mAs and 115 cm SDD, while, 5-year-old; 62 kVp, 8 mAs and 130 cm SDD both included 1 mm Al +0.1 mm Cu additional filtration. The main effect analysis identified situations in which image quality and radiation dose increased or decreased, except for kVp which showed peak image quality when exposure factors were increased. A set of minimum mAs values for producing diagnostic image quality were identified. Increasing SDD, unlike the other exposure factors, showed no trends for producing non-diagnostic images. ConclusionThe factorial design provided an opportunity to identify suitable acquisition factors. This study provided a method for investigating the combined effect of multiple acquisition parameters on image quality and radiation dose for children.

Construction and validation of a low cost paediatric pelvis phantom

PurposeImaging phantoms can be cost prohibitive, therefore a need exists to produce low cost alternatives which are fit for purpose. This paper describes the development and validation of a low cost paediatric pelvis phantom based on the anatomy of a 5-year-old child. MethodsTissue equivalent materials representing paediatric bone (Plaster of Paris; PoP) and soft tissue (Poly methyl methacrylate; PMMA) were used. PMMA was machined to match the bony anatomy identified from a CT scan of a 5-year-old child and cavities were created for infusing the PoP. Phantom validation comprised physical and visual measures. Physical included CT density comparison between a CT scan of a 5-year old child and the phantom and Signal to Noise Ratio (SNR) comparative analysis of anteroposterior phantom X-ray images against a commercial anthropomorphic phantom. Visual analysis using a psychometric image quality scale (face validity). ResultsCT density, the percentage difference between cortical bone, soft tissue and their equivalent tissue substitutes were −4.7 to −4.1% and −23.4%, respectively. For SNR, (mAs response) there was a strong positive correlation between the two phantoms (r > 0.95 for all kVps). For kVp response, there was a strong positive correlation between 1 and 8 mAs (r = 0.85), this then decreased as mAs increased (r = −0.21 at 20 mAs). Psychometric scale results produced a Cronbach’s Alpha of almost 0.8. ConclusionsPhysical and visual measures suggest our low-cost phantom has suitable anatomical characteristics for X-ray imaging. Our phantom could have utility in dose and image quality optimisation studies.

Efficacy and tolerability of moxidectin alone and in co-administration with albendazole and tribendimidine versus albendazole plus oxantel pamoate against Trichuris trichiura infections: a randomised, non-inferiority, single-blind trial

The recommended anthelmintics show low efficacy in a single-dose regimen against Trichuris trichiura. Moxidectin, a new treatment for river blindness, might complement the drug armamentarium for the treatment and control of soil-transmitted helminthiasis. However, its efficacy against T trichiura has not yet been studied. The aim of the study was to assess the efficacy of moxidectin alone and in co-administrations against T trichiura infection. A randomised, single-blind, non-inferiority trial was done in two primary schools and one secondary school in Pemba, Tanzania. Adolescents aged 12-18 years who tested positive for T trichiura were randomly assigned (5:5:3:3) with a computer-generated sequence to receive moxidectin (8 mg) plus albendazole (400 mg), albendazole (400 mg) plus oxantel pamoate (25 mg/kg; reference treatment), moxidectin (8 mg) plus tribendimidine (200 mg or 400 mg), or moxidectin (8 mg) alone. Study group assignments were masked from participants and laboratory technicians. The primary outcome was non-inferiority with a 2 percentage point margin for egg reduction rate (ERR) against T trichiura assessed as the relative change in the geometric mean egg counts from baseline to 14-21 days after treatment with the Kato-Katz method, based on the available case population. Cure rates (CR) and tolerability (assessed 3, 24, and 48 h post treatment) were secondary outcomes. The study is registered at ISRCTN (number 20398469) and is closed to accrual. 701 students were enrolled between April 1, and Aug 7, 2017. Primary outcome data were available for 634 students. We observed ERRs of 98·5% for moxidectin plus albendazole and 99·8% for albendazole plus oxantel pamoate, resulting in an absolute difference of -1·2 percentage points (95% CI -1·8 to -0·8), meeting the non-inferiority margin. 100 (51%) of 197 students receiving moxidectin plus albendazole and 166 (83%) of 200 receiving albendazole plus oxantel pamoate were cured, indicating a difference of 32 percentage points (odds ratio 5·3, 95% CI 3·3 to 8·7). ERRs were 91·6% for moxidectin-tribendimidine and 83·2% for moxidectin. Only mild adverse events (mainly headache and stomach pain) were reported. The largest number of adverse events (126 [20%] of 632 students) was observed 24 h post treatment, with no difference among the individual treatment arms (ranging from 23 [19%] of 118 students treated with moxidectin to 38 [19%] of 199 with moxidectin plus albendazole). Moxidectin plus albendazole showed non-inferiority to albendazole plus oxantel pamoate in terms of ERR; however, albendazole plus oxantel pamoate showed a considerably higher cure rate. Dose-optimisation studies with moxidectin and moxidectin plus albendazole should be considered since the efficacy of the dose used for the treatment of onchocerciasis (8 mg) in this study might not be optimal for the treatment of T trichiura infections. Thrasher Foundation.

FOSMIDOMYCIN-PIPERAQUINE AS NON-ARTEMISININ-BASED COMBINATION FOR ACUTE UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA

BackgroundAs investment in research related to artemisinin resistance is a key objective of the Global Plan for Artemisinin Resistance Containment (GPARC), fosmidomycin and piperaquine are being developed to address the...

A GPU Simulation Tool for Training and Optimisation in 2D Digital X-Ray Imaging.

Conventional radiology is performed by means of digital detectors, with various types of technology and different performance in terms of efficiency and image quality. Following the arrival of a new digital detector in a radiology department, all the staff involved should adapt the procedure parameters to the properties of the detector, in order to achieve an optimal result in terms of correct diagnostic information and minimum radiation risks for the patient. The aim of this study was to develop and validate a software capable of simulating a digital X-ray imaging system, using graphics processing unit computing. All radiological image components were implemented in this application: an X-ray tube with primary beam, a virtual patient, noise, scatter radiation, a grid and a digital detector. Three different digital detectors (two digital radiography and a computed radiography systems) were implemented. In order to validate the software, we carried out a quantitative comparison of geometrical and anthropomorphic phantom simulated images with those acquired. In terms of average pixel values, the maximum differences were below 15%, while the noise values were in agreement with a maximum difference of 20%. The relative trends of contrast to noise ratio versus beam energy and intensity were well simulated. Total calculation times were below 3 seconds for clinical images with pixel size of actual dimensions less than 0.2 mm. The application proved to be efficient and realistic. Short calculation times and the accuracy of the results obtained make this software a useful tool for training operators and dose optimisation studies.

P-glycoprotein-dependent pharmacokinetics of irinotecan and its active metabolite, SN-38 in rats: Effect of verapamil

We have recently demonstrated that the oral bioavailability of irinotecan (80 mg/kg) can be increased at least 7-fold by co-administration of the P-gp blocker verapamil (25 mg/kg, Oral). As a result, co-treatment with P-gp inhibitor could be a useful strategy for bioavailability enhancement. However, in view of narrow therapeutic index, the co-administration of irinotecan and verapamil may result in unanticipated toxicities. Therefore, dose optimisation studies of irinotecan were performed when it is given in conjunction with a P-gp inhibitor. For dose optimization study, the bioavailability and pharmacokinetic parameters were studied in rats after oral administration of irinotecan at three doses (i.e. 20, 40 and 80 mg/kg) alone and in combination with verapamil (25 mg/kg, oral). The area under the plasma-concentration time curve (AUC) of irinotecan at 20, 40 and 80 mg/kg was 3.51 ± 1.20, 8.81 ± 1.93 and 14.03 ± 2.18 h µg/ml, respectively which after treatment with verapamil, increased dose dependently to 7.84 ± 1.20, 19.94 ± 2.39 and 61.71 ± 15.0 h µg/ml, respectively. In addition to irinotecan, plasma concentrations of SN-38, one of the major active metabolite of irinotecan, were also monitored. The less than proportional increase in SN-38 AUC from 20 to 80 mg/kg is consistent with the saturation of carboxylesterase. Our results indicate that oral drug treatment of irinotecan in presence of temporary P-gp inhibition could be as equally safe and effective as intravenous administration. Nevertheless, safe P-gp inhibitors need to be identified as alternatives to verapamil for development of efficacious oral irinotecan formulations.

Optimal dose finding for novel antimalarial combination therapy*

A recent discussion meeting convened by the Medicines for Malaria Venture examined how best to manage the discovery and preclinical pipeline to achieve novel combination therapies which would address the key clinical needs in malaria. It became clear that dose optimisation of components within combination therapy was a key issue in achieving antimalarial efficacy and for preserving that efficacy against parasite resistance emergence. This paper outlines some of the specific issues in malaria that cause dose-ranging and dose-optimisation studies to be particularly challenging and discusses the potential of factorial study design to address such challenges.

A simple phantom study of the effects of dose reduction (by kVp increment) below current dose levels on CR chest image quality

Purpose To assess the applicability of a simple commercial chest phantom incorporating a quasi anthropomorphic insert, in image quality and dose optimisation studies in computed radiography (CR). Methods Lung and mediastinal lesions simulated with gelatine were positioned on the chest phantom and exposures made at the current chest radiography dose, set as D ref in the study. Further exposures were made at doses below D ref to study the effect of reducing patient dose below current dose levels, on the clarity and detectability of lung lesions in computed radiography. Lesion detectability and clarity was assessed by four observers using a commercial image viewing software without image manipulation, and a local image viewing software that allowed image contrast enhancement. The possibility of extending dose reduction below current dose levels (D ref) was assessed for both unmanipulated and manipulated images, from comparison of doses that produced statistically significant differences in image quality from D ref. Results Results show that as the dose was decreased below D ref, both the clarity and detectability of lesions in the lung images worsened when there was no facility to manipulate the image. The onset of a significant difference in image clarity in the lung area occurred at 0.06 mGy while significant detectability changes were observed at 0.04 mGy. Similar changes in image quality were observed with the use of image manipulation. However, dose reduction produced statistically significant differences ( p < 0.05) in both image clarity and detectability at 0.10 mGy. Image clarity and detectability in the mediastinal area showed no statistical difference at all doses ( p > 0.05) with and without image manipulation. Conclusion The clarity and detectability of lesion images as a function of patient doses in computed radiography may be dependent on whether or not contrast enhancement techniques are employed. There is also evidence to suggest that low dose images of the high density mediastinum can be enhanced with post processing, making exposure at high doses unnecessary. Further work and clinical trials would be needed to confirm the generalizablity of these findings.

Cu filtration for dose reduction in neonatal chest imaging

As neonatal chest images are frequently acquired to investigate the life-threatening lung diseases in prematurely born children, their optimisation in terms of X-ray exposure is required. The aim of this study was to investigate whether such dose-optimisation studies could be performed using a Monte Carlo computer model. More specifically, a Monte Carlo computer model was used to investigate the influence of Cu filtration on image quality and dose in neonatal chest imaging. Monte Carlo simulations were performed with the MCNPX code and used with voxel models representing prematurely born babies (590 and 1910 g). Physical image quality was derived from simulated images in terms of the signal difference-to-noise ratio and signal-to-noise ratio (SNR). To verify the simulation results, measurements were performed using the Gammex 610 Neonatal Chest Phantom, which represents a 1-2 kg neonate. A figure of merit was used to assist in evaluating the optimum balance between the image quality and the patient dose. The results show that the Monte Carlo computer model to investigate dose and image quality works well and can be used in dose-optimisation studies for real clinical practices. Furthermore, working at a specific constant incident air kerma (K(a,I)), additional filtration proved to increase SNR with 30 %, whereas working at a specific constant detector dose, extra Cu filtration reduces the lung dose with 25 %. Optimum balance between patient dose and image quality is found to be 60 kVp (using extra filtration).

Dasatinib for the treatment of Philadelphia chromosome-positive chronic myelogenous leukaemia after imatinib failure

Dasatinib, a potent, oral kinase inhibitor, is presently approved for Philadelphia-positive chronic myelogenous leukaemia (CML) following imatinib failure. In an in vitro study, dasatinib had 325-fold greater potency than imatinib for inhibiting unmutated BCR-ABL. Phase I and II data show that dasatinib 70 mg b.i.d. is effective after imatinib failure in various phases of CML. Comparative data of dasatinib versus high-dose imatinib in patients with resistance or intolerance to imatinib demonstrated that dasatinib was associated with improved response rates and progression-free survival. Side effects of dasatinib, including pleural effusions, are manageable with modification of dose or schedule. Phase III dose optimisation studies and future indications are also discussed.

Pharmacokinetics of dihydroartemisinin following oral artesunate treatment of pregnant women with acute uncomplicated falciparum malaria

To determine the pharmacokinetic properties of dihydroartemisinin (DHA) following oral artesunate treatment in women with recrudescent multi-drug resistant falciparum malaria, in the second and third trimesters of pregnancy. Serial plasma concentrations of artesunate and DHA were measured in 24 women after the final dose of a 3 day treatment with artesunate (4 mg kg(-1) day(-1)) and atovaquone (20 mg kg(-1) day(-1)) plus proguanil (8 mg kg(-1) day(-1)), daily. Conventional non-compartmental modelling and a population one-compartment pharmacokinetic model were applied to the data. Artesunate was very rapidly eliminated. For DHA the median [90% range] estimate of oral clearance (CI/F) was 4.0 [0.8-20.7] l hour(-1) kg(-1), total apparent volume of distribution (Vd/f) was 3.4 [0.9-60.7] l/kg, and terminal elimination half-life was 1.0 [0.6-2.4] h. The kinetics of DHA are modified by pregnancy. The plasma levels of the active antimalarial metabolite DHA are lower than reported previously in non-pregnant adults. Dose-optimisation studies in pregnant women are needed.