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ABSTRACT With the development of targeted therapy, immunotherapy, and antibody‐drug conjugates (ADCs), there is growing concern over the “more is better” paradigm developed decades ago for chemotherapy, prompting the US Food and Drug Administration (FDA) to initiate Project Optimus to reform dose optimization and selection in oncology drug development. For early‐phase oncology trials, given the high variability from sparse data and the rigidity of parametric model specifications, we use Bayesian dynamic models to borrow information across doses with only vague order constraints. Our proposed adaptive design simultaneously incorporates toxicity and efficacy outcomes to select the optimal dose (OD) in Phase I/II clinical trials, utilizing Bayesian model averaging to address the uncertainty of dose–response relationships and enhance the robustness of the design. Additionally, we extend the proposed design to handle delayed toxicity and efficacy outcomes. We conduct extensive simulation studies to evaluate the operating characteristics of the proposed method under various practical scenarios. The results demonstrate that the proposed designs have desirable operating characteristics. A trial example is presented to demonstrate the practical implementation of the proposed designs. [ABSTRACT FROM AUTHOR]

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The aim of this study was to evaluate a natural coagulant, Moringa oleifera seeds (MOC), to reduce the color concentration in treated tequila vinasses (TVs). TV-A was the effluent of horizontal subsurface flow wetlands (HSSFW); TV-B was the effluent of vertical up-flow wetlands (VUFW); and TV-C was the effluent of vertical down-flow constructed wetlands (VDFW). Raw TVs were also evaluated with MOC. Jar tests were performed to find the optimal dose and pH value for apparent color (AC) removal. With the optimal dose and pH for each type of TV, tests were performed in triplicate to evaluate the removal of apparent color (AC), true color (TC), turbidity, total suspended solids (TSS), chemical oxygen demand (COD), and electrical conductivity (EC). For TV-A and TV-B, the optimal values were 1 g/L of MOC and pH 8, and the removals were 52%, 43%, 50% and 72% of AC, turbidity, TC, and TSS, respectively. For TV-C, the optimal values were 2.5 g/L and pH 5, with removals of 66%, 73%, and 98% for AC, TC, and TSS, respectively. For TV-D, the MOC had no coagulant effect in any of the experimental conditions evaluated, probably due to the high concentration of turbidity and TSS in the raw vinasses, which prevented the interaction between MOC and melanoidins. Deeper studies are required to understand and evaluate those factors that influence MOC efficiency so that the coagulation–flocculation process can be optimized. [ABSTRACT FROM AUTHOR]

Objective To investigate the application efficacy and optimal dosage of dexmedetomidine preconditioning in modified electroconvulsive therapy (MECT) and to explore its optimal dose. Methods Two hundred and fifty-two patients who were to undergo MECT were selected and were randomly divided into group D1, group D2, group D3, group D4, group D5 and control group, respectively, with 42 cases in each. Ten min before anaesthesia induction, 0. 2, 0. 4, 0. 6, 0. 8 and 1. 0 µg/kg dexmedetomidine hydrochloride was intravenously pumped into the D1, D2, D3, D4 and D5 groups, respectively, and the control group was intravenously pumped with an equal volume of normal saline 30 mL; the patients were treated by a MECT therapeutic instrument. Heart rate (HR) and mean arterial pressure (MAP) were recorded in each group at the immediate moment of dexmedetomidine pretreatment (T1), 5 min after pretreatment (T2), 10 min after pretreatment (T3), 15 min after pretreatment (T4), 20 min after pretreatment (T5), 25 min after pretreatment (T6), and 30 min after pretreatment (T7), respectively; and the duration of seizure, the dose of propofol used during MECT, the recovery time of spontaneous respiration, the awakening time and the occurrence of adverse reactions were compared between the groups. Results Compared with the control group at the same time point, HR was reduced in the group D1 at T4, and in the groups D2, D3, D4, and D5 at T2 to T7; and MAP was reduced in the group D2 at T4 to T7, and in the groups D3, D4, and D5 at T2 to T7 (all P<0. 05) . Compared with the same group at T1, HR was reduced in the groups D4 and D5 at T7; MAP was reduced in the groups D3, D4 and D5 at T7 (all P<0. 05) . There was no statistically significant difference in seizure duration among groups (all P>0. 05) ; the dosage of propofol was less in the groups D2, D3, D4, and D5 than in the control group; the recovery time of spontaneous respiration was longer in the groups D4 and D5 than in the control group; the time of awakening was longer in the groups D3, D4, and D5 than in the control group; and the incidence rate of adverse reactions was lower in the groups D1, D2, D3, D4, and D5 than in the control group (all P<0. 05) . Comclusion Dexmedetomidine pretreatment can effectively reduce the haemodynamic fluctuation of MECT patients, reduce the dose of anaesthesia drugs, improve the quality of anaesthesia recovery, and has better safety; in MECT, pretreatment with 0. 4 µg/kg dexmedetomidine has the best effect. [ABSTRACT FROM AUTHOR]

Abstract The purpose of this study was to review the literature on the clinical use of voriconazole (VRC) in pediatric patients. MEDLINE, Embase, PubMed, Web of Science, and Cochrane Library were searched from January 1, 2000, to August 15, 2023 for relevant clinical studies on VRC use in pediatric patients. Data were collected based on inclusion and exclusion criteria, and a systematic review was performed on recent research related to the use of VRC in pediatric patients. This systematic review included a total of 35 observational studies among which there were 16 studies investigating factors influencing VRC plasma trough concentrations (Ctrough) in pediatric patients, 14 studies exploring VRC maintenance doses required to achieve target range of Ctrough, and 11 studies focusing on population pharmacokinetic (PPK) research of VRC in pediatric patients. Our study found that the Ctrough of VRC were influenced by both genetic and non-genetic factors. The optimal dosing of VRC was correlated with age in pediatric patients, and younger children usually required higher VRC doses to achieve target Ctrough compared to older children. Establishing a PPK model for VRC can assist in achieving more precise individualized dosing in children.

The purpose of this study was to review the literature on the clinical use of voriconazole (VRC) in pediatric patients. MEDLINE, Embase, PubMed, Web of Science, and Cochrane Library were searched from January 1, 2000, to August 15, 2023 for relevant clinical studies on VRC use in pediatric patients. Data were collected based on inclusion and exclusion criteria, and a systematic review was performed on recent research related to the use of VRC in pediatric patients. This systematic review included a total of 35 observational studies among which there were 16 studies investigating factors influencing VRC plasma trough concentrations (Ctrough) in pediatric patients, 14 studies exploring VRC maintenance doses required to achieve target range of Ctrough, and 11 studies focusing on population pharmacokinetic (PPK) research of VRC in pediatric patients. Our study found that the Ctrough of VRC were influenced by both genetic and non-genetic factors. The optimal dosing of VRC was correlated with age in pediatric patients, and younger children usually required higher VRC doses to achieve target Ctrough compared to older children. Establishing a PPK model for VRC can assist in achieving more precise individualized dosing in children. [ABSTRACT FROM AUTHOR]

The U.S. Food and Drug Administration launched Project Optimus with the aim of shifting the paradigm of dose-finding and selection toward identifying the optimal biological dose that offers the best balance between benefit and risk, rather than the maximum tolerated dose. However, achieving dose optimization is a challenging task that involves a variety of factors and is considerably more complicated than identifying the maximum tolerated dose, both in terms of design and implementation. This article provides a comprehensive review of various design strategies for dose-optimization trials, including phase 1/2 and 2/3 designs, and highlights their respective advantages and disadvantages. In addition, practical considerations for selecting an appropriate design and planning and executing the trial are discussed. The article also presents freely available software tools that can be utilized for designing and implementing dose-optimization trials. The approaches and their implementation are illustrated through real-world examples. [ABSTRACT FROM AUTHOR]

Background: Intravenously administered indocyanine green (ICG) accumulates in lung tumors, facilitating their detection via a fluorescence spectrum measurement. This method aids in identifying tumor locations that are invisible to the naked eye. We aim to determine the optimal ICG dose and administration method for accurate tumor identification during lung resection surgeries, utilizing a novel ICG fluorescence spectroscopy system for precise tumor localization. Materials and Methods: ICG should be dissolved in the provided solution or distilled water and administered intravenously approximately 24 h before surgery, beginning with an initial dose of 0.5 mg/kg. If the tumor detection rate is insufficient, the dose may be gradually increased to a maximum of 5.0 mg/kg to determine the optimal dosage for effective tumor detection. This fluorescence spectroscopy during surgery may reveal additional lesions that remain undetected in preoperative assessments. The primary endpoint includes the correct diagnostic rate of tumor localization. The secondary endpoints include the measurement of the intraoperative ICG fluorescence spectral intensity in lung tumors, the assessment of the operability and safety of intraperitoneal ICG administrations, the measurement of the ICG fluorescence spectral intensity in surgical specimens, the comparison of the spectral intensity in lung tissues during collapse and expansion, the correlation between ICG camera images and fluorescence spectral intensity, and the comparison of fluorescence analysis results with histopathological findings. The trial has been registered in the jRCT Clinical Trials Registry under the code jRCTs011230037. Results and Conclusions: This trial aims to establish an effective methodology for localizing and diagnosing malignant lung tumors, thereby potentially improving surgical outcomes and refining treatment protocols. [ABSTRACT FROM AUTHOR]

Tuta absoluta (Meyrick) is a destructive pest of tomato crops. The cryptic nature of larvae often leads to low control efficacy. Sterile insect technique (SIT) has the potential to be an alternative management option for T. absoluta. In this study, the optimal dose for T. absoluta sterility was determined by estimating the effect of gamma radiation on parental generation (F0) and their descendants (first and second generation, F1 and F2). Adult emergence was not affected when T. absoluta pupae were exposed to gamma radiation at doses of 100~400 Gy. However, increasing doses of radiation increased deformed individuals and shortened their longevity. Furthermore, as the dose increased, F0 females showed decreased fecundity and fertility, and they were completely sterile when exposed to 300 Gy. The survival and sex ratio of females declined significantly in F1 of irradiated males with increasing doses. Moreover, we found that 300 Gy of gamma radiation did not affect the mating competitiveness of F0 males. Interestingly, this treatment caused a considerable reduction in the number of descendants and caused inherited sterility in F1 by lowering their fecundity and fertility. Therefore, the optimal radiation dose was 300 Gy, and the release of sterile adults may suppress T. absoluta population growth in the field. Our findings provide basis for controlling T. absoluta through SIT programs. [ABSTRACT FROM AUTHOR]

68Ga-satoreotide trizoxetan is a novel somatostatin receptor antagonist associated with high sensitivity and reproducibility in neuroendocrine tumor (NET) detection and localization. However, the optimal peptide mass and radioactivity ranges for 68Ga-satoreotide trizoxetan have not yet been established. We therefore aimed to determine its optimal dosing regimen in patients with metastatic gastroenteropancreatic NETs in a prospective, randomized, 2 × 3 factorial, multicenter phase II study. Methods: Patients received 68Ga-satoreotide trizoxetan at a peptide mass of 5-20 µg on day 1 of the study and of 30-45 µg on days 16-22, at 1 of 3 68Ga radioactivity ranges (40-80, 100-140, or 160-200 MBq). Whole-body PET/CT imaging was performed 50-70 min after each injection. The primary endpoint was the detection rate of NET lesions imaged by 68Ga-satoreotide trizoxetan relative to contrast-enhanced CT (for each of the 6 peptide mass and radioactivity range combinations). Results: Twenty-four patients were evaluated in the per-protocol analysis. The median number of lesions detected by 68Ga-satoreotide trizoxetan PET/CT or PET alone was at least twice as high as the number detected by contrast-enhanced CT across the 6 studied peptide mass and radioactivity range combinations. There were no differences between the 2 peptide mass ranges or between the 3 radioactivity ranges in the number of identified lesions. However, a trend toward a lower relative lesion count was noted in the liver for the 40- to 80-MBq range. No relationship was observed between the radioactivity range per patient's body weight (MBq/kg) and the number of lesions detected by 68Ga-satoreotide trizoxetan. The median diagnostic sensitivity of 68Ga-satoreotide trizoxetan PET/CT, based on the number of lesions per patient, ranged from 85% to 87% across the different peptide mass and radioactivity ranges. Almost all reported adverse events were mild and self-limiting. Conclusion: A radioactivity of 100-200 MBq with a peptide mass of up to 50 µg was confirmed as the optimal dosing regimen for 68Ga-satoreotide trizoxetan to be used in future phase III studies.

Background and Objective: Total hip arthroplasty [THA] is frequently performed in Egypt for patients with degenerative joint disease. This procedure is performed under general anaesthesia and is associated with severe postoperative pain. Pregabalin has been described as an effective adjuvant for spinal anaesthesia. However, its optimum dose has not been standardized. Herein, we compared two different pregabalin doses [150 and 300 mg] regarding spinal anaesthesia characteristics and postoperative analgesic outcomes.Patients and Methods: One hundred people who were going to have THA were enrolled in this prospective study. They were split into two groups at random: Group A had 50 people who took 150 mg pregabalin capsules an hour before the surgery, and Group B had 50 people who took 300 mg pregabalin capsules at the same time.Results: Preoperative patient criteria did not differ between the two groups. Moreover, sensory block criteria, including time to reach the T10 block, peak sensory block level, and time to reach it, were also comparable between the two groups. Nonetheless, the motor block duration increased in Group B. The majority of the recorded pain scores after the operation significantly decreased in Group B during the first postoperative day. Group B showed a significant elongation of the time to the first analgesic request and a significant decline in postoperative morphine consumption.Conclusion: When THA is done with spinal anaesthesia and 300 mg of pregabalin is taken by mouth, the pain relief is much better than when 150 mg is taken.

Background Candida auris isolates exhibit elevated amphotericin B (AMB) minimum inhibitory concentrations (MICs). As liposomal AMB (L-AMB) can be safely administered at high doses, we explored L-AMB pharmacodynamics against C. auris isolates in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) dilution model. Methods Four C. auris isolates with Clinical and Laboratory Standards Institute (CLSI) AMB MICs = 0.5–2 mg/L were tested in an in vitro PK/PD model simulating L-AMB pharmacokinetics. The in vitro model was validated using a Candida albicans isolate tested in animals. The peak concentration (Cmax)/MIC versus log10 colony-forming units (CFU)/mL reduction from the initial inoculum was analyzed with the sigmoidal model with variable slope (Emax model). Monte Carlo analysis was performed for the standard (3 mg/kg) and higher (5 mg/kg) L-AMB doses. Results The in vitro PK/PD relationship Cmax/MIC versus log10 CFU/mL reduction followed a sigmoidal pattern (R2 = 0.91 for C. albicans , R2 = 0.86 for C. auris). The Cmax/MIC associated with stasis was 2.1 for C. albicans and 9 for C. auris. The probability of target attainment was >95% with 3 mg/kg for wild-type C. albicans isolates with MIC ≤2 mg/L and C. auris isolates with MIC ≤1 mg/L whereas 5 mg/kg L-AMB is needed for C. auris isolates with MIC 2 mg/L. Conclusions L-AMB was 4-fold less active against C. auris than C. albicans. Candida auris isolates with CLSI MIC 2 mg/L would require a higher L-AMB dose. [ABSTRACT FROM AUTHOR]

In the era of targeted therapy, there has been increasing concern about the development of oncology drugs based on the "more is better" paradigm, developed decades ago for chemotherapy. Recently, the US Food and Drug Administration (FDA) initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. To accommodate this paradigm shifting, we propose a dose‐ranging approach to optimizing dose (DROID) for oncology trials with targeted drugs. DROID leverages the well‐established dose‐ranging study framework, which has been routinely used to develop non‐oncology drugs for decades, and bridges it with established oncology dose‐finding designs to optimize the dose of oncology drugs. DROID consists of two seamlessly connected stages. In the first stage, patients are sequentially enrolled and adaptively assigned to investigational doses to establish the therapeutic dose range (TDR), defined as the range of doses with acceptable toxicity and efficacy profiles, and the recommended phase 2 dose set (RP2S). In the second stage, patients are randomized to the doses in RP2S to assess the dose–response relationship and identify the optimal dose. The simulation study shows that DROID substantially outperforms the conventional approach, providing a new paradigm to efficiently optimize the dose of targeted oncology drugs. DROID aligns with the approach of a randomized, parallel dose‐response trial design recommended by the FDA in the Guidance on Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases. [ABSTRACT FROM AUTHOR]

The primary objective of an oncology dose‐finding trial for novel therapies, such as molecularly targeted agents and immune‐oncology therapies, is to identify the optimal dose (OD) that is tolerable and therapeutically beneficial for subjects in subsequent clinical trials. Pharmacokinetic (PK) information is considered an appropriate indicator for evaluating the level of drug intervention in humans from a pharmacological perspective. Several novel anticancer agents have been shown to have significant exposure‐efficacy relationships, and some PK information has been considered an important predictor of efficacy. This paper proposes a Bayesian optimal interval design for dose optimization with a randomization scheme based on PK outcomes in oncology. A simulation study shows that the proposed design has advantages compared to the other designs in the percentage of correct OD selection and the average number of patients allocated to OD in various realistic settings. [ABSTRACT FROM AUTHOR]

Introduction: While vancomycin remains awidely prescribed antibiotic, it can cause ototoxicity and nephrotoxicity, both of which are concentration-associated. Overtreatment can occur when the treatment lasts for an unnecessarily long time. Using a model-informed precision dosing scheme, this study aims to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for vancomycin to determine the optimal dosage regimen and treatment duration in order to avoid drug-induced toxicity. Methods: The data were obtained from electronic medical records of 542 patients, including 40 children, and were analyzed using NONMEM software. For PK, vancomycin concentrations were described with a two-compartment model incorporating allometry scaling. Results and discussion: This revealed that systemic clearance decreased with creatinine and blood urea nitrogen levels, history of diabetes and renal diseases, and further decreased in women. On the other hand, the central volume of distribution increased with age. For PD, C-reactive protein (CRP) plasma concentrations were described by transit compartments and were found to decrease with the presence of pneumonia. Simulations demonstrated that, given the model informed optimal doses, peak and trough concentrations as well as the area under the concentration-time curve remained within the therapeutic range, even at doses smaller than routine doses, for most patients. Additionally, CRP levels decreased more rapidly with the higher dose starting from 10 days after treatment initiation. The developed R Shiny application efficiently visualized the time courses of vancomycin and CRP concentrations, indicating its applicability in designing optimal treatment schemes simply based on visual inspection. [ABSTRACT FROM AUTHOR]

Organic fertilizers are beneficial and less expensive if applied in adequate doses. This is how the present investigation aims to determine the optimal quantity of manure from laying hens to apply to oil palm trees in the prenursery and in the nursery. To do this, different proportions of manure from laying hens combined with those of potting soil constituted the treatments applied to oil palms. Growth parameters such as collar diameter, length of longest leaf, number of leaves emitted, and height of seedlings and plants were assessed. The results obtained showed that, regardless of the growth parameter, the maximum values ​​were recorded at a dose of 6.67% of laying hen manure, i.e. one volume of laying hen manure for 14 volumes of potting soil and at the dose of 16.67% of laying hen manure, i.e. one volume of laying hen manure for 5 volumes of potting soil for the prenursery and nursery stages, respectively. On the other hand, the growth parameters suffered from the effects of overdoses of manure from laying hens which ended up becoming toxic and even lethal to the plants. In this study, one volume of laying hen manure for 14 volumes of potting soil and one volume of laying hen manure for 5 volumes of potting soil were respectively retained as optimal quantities for the prenursery and nursery stages, respectively. [ABSTRACT FROM AUTHOR]

Background: Evidence regarding the effectiveness of melatonin receptor agonists in treating delayed sleep-wake phase disorder (DSWPD) remains limited. This study aimed to determine the optimal dose of ramelteon, a melatonin receptor agonist, for the better treatment adherence of DSWPD. Methods: The patients who were diagnosed definitely as having DSWPD by board-certified physicians specialized in sleep medicine and started to receive strategically timed ramelteon medications after the diagnosis were included. Data on the initial ramelteon dose and follow-up duration (up to 24 months) were collected retrospectively. Patients with treatment discontinuation, changes in ramelteon dose, or the addition of other sleep-related medications were considered dropouts. Kaplan-Meier estimates, log-rank tests, and Cox regression analyses were performed. Results: Overall, 373 patients were analyzed. The findings revealed that the 2 mg dose of ramelteon was associated with a lower dropout rate compared to the other doses (8 mg, 4 mg, and 1 mg). The dropout rate for the 2 mg group was estimated to have a hazard ratio (HR) of 0.5762 when compared with the 8 mg dose group. Sex did not reveal a significant HR, whereas older age exhibited a small but significant HR (0.9858). Conclusion: For achieving better adherence, a dosing regimen of strategically timed 2 mg ramelteon may be the best for the treatment of DSWPD. The therapeutic dose window for better adherence seems to center approximately 2 mg of ramelteon. Furthermore, caution should be exercised when treating younger patients to prevent dropouts. [ABSTRACT FROM AUTHOR]

Background: Amrubicin (AMR) is one of the most active agents for small-cell lung cancer (SCLC). However, hematologic toxicity and infection at a commonly used dose (40 mg/m2) is problematic; the optimal dose remains undetermined. Patients and methods: To evaluate the optimal dose of AMR in terms of efficacy and safety, we reviewed consecutive data on patients with relapsed SCLC who received AMR at doses of 40, 35, and 30 mg/m2 (on days 1–3) at Nippon Medical School Hospital between October 2010 and November 2021. Results: We reviewed the data of 86 patients (20, 45, 27 who received AMR doses of 40, 35, 30 mg/m2, respectively) according to our study criteria. For patients ≥ 75 years, the proportion who received second-line treatment tended to be higher in the 30–35 mg/m2 group. Objective response rates were 37/46/35%, median progression-free survival (PFS) were 3.0/4.7/3.2 months, and median overall survival (OS) were 7.8/16.3/8.0 months, respectively. Grade 4 neutropenia occurred in 58/39/31% of patients, which was higher for the 40 mg/m2 group. The incidence of febrile neutropenia did not differ between groups. Multivariate analysis identified the AMR dose was not associated with longer PFS and OS. Conclusion: Treatment with AMR between 30 and 35 mg/m2 showed relatively mild hematologic toxicity compared with AMR at 40 mg/m2, without any significant difference in efficacy. Lower dose of AMR for relapsed SCLC could be a promising treatment option. [ABSTRACT FROM AUTHOR]

It has become quite common in recent early oncology trials to include both the dose-finding and the dose-expansion parts within the same study. This shift can be viewed as a seamless way of conducting the trials to obtain information on safety and efficacy hence identifying an optimal dose (OD) rather than just the maximum tolerated dose (MTD). One approach is to conduct a dose-finding part based solely on toxicity outcomes, followed by a dose expansion part to evaluate efficacy outcomes. Another approach employs only the dose-finding part, where the dose-finding decisions are made utilizing both the efficacy and toxicity outcomes of those enrolled patients. In this paper, we compared the two approaches through simulation studies under various realistic settings. The percentage of correct ODs selection, the average number of patients allocated to the ODs, and the average trial duration are reported in choosing the appropriate designs for their early-stage dose-finding trials, including expansion cohorts. [ABSTRACT FROM AUTHOR]

Jatropha curcas (JC) is a highly effective conditioner in dewatering fecal sludge (FS); however, there are limited studies on the model predicting its optimal dose. This study presents the results of the developed model for predicting JC optimal doses. The developed model assessed the FS parameters and JC stock solution. We analyzed the FS samples from a mixture of a pit latrine and septic tank at the water quality laboratory of the University of Dar es Salaam. The multiple linear regression model was used to establish a relationship between JC optimal dose as a function of FS characteristics (pH, electrical conductivity, total solids, total suspended solids and concentration of the JC stock solution). The results indicated that 90.4% of the JC optimum dosage was determined and contributed by FS characteristics and JC stock solution concentrations. Also, the main explanatory factors determining the JC optimal dose were the JC stock solution concentration, followed by the pH of FS. The model results showed a good agreement between the predicted and observed JC optimal dose with a coefficient of determination of R2 = 0.904 and 0.7879 for calibration and validation, respectively. Therefore, the model can be adapted to determine the JC optimal dose without running the jar test experiment. HIGHLIGHTS Effects of physical–chemical characteristics of fecal sludge on Jatropha curcas dose.; Physical–chemical predictor of fecal sludge on dewaterability.; Concentration of J. curcas solution on the optimal dose of J. curcas.; J. curcas optimal dose model.; J. curcas optimal modal validation.;

Aim of the study: To develop a method to optimize the pesticide dose considering the combined influence of plant, pest, pesticide, and spray equipment on bioefficacy. Area of study: Agricultural Engineering College and Research Institute, Tamil Nadu Agricultural University, Coimbatore, India. Material and methods: A controlled droplet applicator generated droplets from 200 to 50 μm. The target leaf's deposition density of a preset droplet size can be controlled by timing the spray. A sequence of bioassays was performed at various droplet densities at each pesticide (imidachloprid 17.8% SL) dose and droplet size to determine the mortality of cotton aphids (Aphis gossypii) and jassids (Amrasca biguttula) feeding on immature cotton plants. Calculating the number of droplets per target area needed to cause 50% and 90% mortality (LN50 and LN90) yielded a series of model curves. Field tests were done on the computed optimal doses of the pesticide for a spray apparatus (electrostatically charged spray) to assess the spray's bioefficacy against A. gossypii and A. biguttula. Main results: In comparison to uncharged mist blower spray, which had a bioefficacy of 91% for an LN90 dose of 110 g a.i. L-1, the spray had an 89% bioefficacy on A. gossypii. Using the electrostatic spray, it was 91% effective against A. biguttula and 98% effective against an uncharged mist blower at a dose of 110 g a.i. L-1 of LN90. Research highlights: This generalized method of modelling could effectively compute the optimal pesticide dose for any plant, pest, pesticide, and spray equipment combination.

Background: Intracerebral haemorrhage (ICH) can be devastating, particularly if haematoma expansion occurs. The efficacy of tranexamic acid (TXA), an anti-fibrinolytic agent, in reducing haematoma expansion is now being studied worldwide. However, the optimal dosage of TXA has yet to be determined. This study was designed to further establish the potential of different doses of TXA. Methods: A double-blinded, randomised, placebo-controlled study was carried out among adults with non-traumatic ICH. Eligible study subjects were randomly assigned to receive placebo, 2-g TXA treatment or 3-g TXA treatment. Haematoma volumes before and after intervention were measured using the planimetric method. Results: A total of 60 subjects with 20 subjects in each treatment group were recruited for this study. Among the 60 subjects, the majority were male (n = 36, 60%), had known cases of hypertension (n = 43, 71.7%) and presented with full Glasgow coma scale (GCS) (n = 41, 68.3%). The results showed that there was no statistically significant difference (P = 0.315) in the mean changes of haematoma volume when compared with three study groups using ANCOVA, although the 3-g TXA group was the only group that showed haematoma volume reduction (mean reduction of 0.2 cm3) instead of expansion as in placebo (mean expansion 1.8 cm3) and 2-g TXA (mean expansion 0.3 cm3) groups. Good recovery was observed in all study groups, with only three subjects being moderately disabled. No adverse effects were reported in any of the study groups. Conclusion: To the best of our knowledge, this is the first clinical study using 3 g of TXA in the management of non-traumatic ICH. From our study, 3 g of TXA may potentially be helpful in reducing haematoma volume. Nonetheless, a larger-scale randomised controlled trial should be carried out to further establish the role of 3 g of TXA in non-traumatic ICH. [ABSTRACT FROM AUTHOR]

The present study investigated the effectiveness of two biopolymer coagulants on turbidity and chemical oxygen demand removal in urban wastewater. The biopolymers were produced from vegetal biomass using the mucilage extracted from Opuntia robusta cladodes, and Uncaria tomentosa leaves. Opuntia robusta is an abundant species in Mexico, which is not edible. Uncaria tomentosa is an exotic invasive species in Mexico and other countries, which negatively affects the ecosystems where it is introduced. A combined experimental design of mixture–process was selected to evaluate the effectiveness of both biopolymer coagulants regarding aluminum sulfate (conventional chemical coagulant). Results showed turbidity and chemical oxygen demand removal efficiencies of 42.3% and 69.6% for Opuntia robusta and 17.2% and 39.4% for Uncaria tomentosa biopolymer coagulant, respectively, at a dose of 200 mg/L. Furthermore, optimum conditions from the experimental design to reach the maximum turbidity and chemical oxygen demand removal were obtained at an Opuntia robusta biopolymer coagulant concentration of 10 mg/L, showing removal efficiencies of 68.7 ± 1.7% and 86.1 ± 1.4%, respectively. These results support using Opuntia robusta as an alternative biopolymer coagulant in urban wastewater treatment. [ABSTRACT FROM AUTHOR]

Introduction: Over the past few decades, advances in traumatic brain injury (TBI) pathology research have dynamically enriched our knowledge. Therefore, we aimed to systematically elucidate the safety and efficacy of erythropoietin (EPO) dosing regimens in patients with TBI. Methods: Data search included PubMed, the Cochrane Library, Embase, Web of Science, and ClinicalTrials.gov for related research published before July 2022. The network meta-analysis was conducted using ADDIS 1.16.8, and the CINeMA tool was used to assess the quality level of evidence. Results: A total of six RCTs involving 981 patients were included in the network meta-analysis. EPO did not significantly reduce mortality in patients with TBI, but its risk of death decreased with increasing dosage (odds ratio (OR) of 12,000u vs. placebo = 0.98, 95% CI: 0.03-40.34; OR of group 30,000u vs. placebo = 0.56, 95% CI: 0.06-5.88; OR of 40,000u vs. placebo = 0.35, 95% CI: 0.01-9.43; OR of 70,000u vs. placebo = 0.29, 95% CI: 0.01-9.26; OR of group 80,000u vs. placebo = 0.22, 95% CI: 0.00-7.45). A total of three studies involving 739 patients showed that EPO did not increase the incidence of deep vein thrombosis in patients with TBI. However, the risk tended to rise as the dosage increased. Another two studies demonstrated that EPO did not increase the incidence of pulmonary embolism. The quality of evidence for all outcomes was low to moderate. Conclusion: Although the efficacy of EPO was not statistically demonstrated, we found a trend toward an association between EPO dosage and reduced mortality and increased embolic events in patients with TBI. More high-quality original studies should be conducted to obtain strong evidence on the optimal dosage of EPO. [ABSTRACT FROM AUTHOR]

Moringa Oleifera (MO) is a highly effective conditioner in the dewatering of Fecal sludge (FS). However, the model for the prediction of its optimal dose has not yet been documented. This article presents the results of the developed model for the prediction of MO optimal doses. The developed model was based on assessing the FS parameters and MO stock solution. The FS samples were obtained from a mixture of a pit latrine and septic tank and were analyzed at the water quality laboratory of the University of Dar es Salaam. The multiple linear regression model was used to establish a relationship between MO optimal dose as a function of FS characteristics (pH, Electrical Conductivity, Total Solids and Total Suspended Solids) and concentration of MO stock solution. The results indicated that the main contributing factors which determine the MO optimal dose were the concentration of MO stock solution, followed by pH of FS. The model results showed a good agreement between the predicted and observed MO optimal dose with a coefficient of determination of R2 = 0.72 and 0.9 for calibration and validation respectively. Therefore, the model can be adapted to determine the MO optimal dose without running the Jar-test experiment. HIGHLIGHTS Effect of physical-chemical Faecal sludge characteristics on Moringa Oleifera dose.; Physical-chemical predictor of Faecal sludge dewaterability.; Concentration of Moringa Oleifera solution on optimal dose of Moringa Oleifera.; Moringa Oleifera optimal dose model.; Moringa Oleifera optimal model validation.;

Background: Intravenous recombinant tissue plasminogen activator (r-tPA) with 0.9 mg/kg is the standard treatment for acute ischemic stroke, but it remains unclear whether it is optimal for all patients. We aimed to determine the optimal dose of r-tPA for Chinese stroke based on the data from the INTRECIS study. Methods: From the INTRECIS cohort, patients receiving intravenous r-tPA within 4.5 h of onset were included. According to r-tPA dose, patients were assigned into seven groups (from 0.60 to 0.90 mg/kg). The primary outcomes were the proportion of excellent functional outcomes and symptomatic intracranial hemorrhage. Results: Overall, 2,666 patients were included: 156 in 0.60 mg/kg group, 117 in 0.65 mg/kg group, 127 in 0.70 mg/kg group, 188 in 0.75 mg/kg group, 154 in 0.80 mg/kg group, 359 in 0.85 mg/kg group, and 1,565 in 0.90 mg/kg group. After adjustment for baseline characteristics, only 0.65 mg/kg group had significantly higher proportion of excellent functional outcome than 0.90 mg/kg group (79.5 vs. 71.4%, odds ratio = 1.833, 95% CI = 1.006-3.341, adjusted p = 0.048). The subgroup analysis showed no evidence of differences in the odds of having a primary outcome between the two groups by age, admission NIHSS, onset to thrombolysis time, and TOAST classification. There was no significant difference in symptomatic intracranial hemorrhage between groups. Conclusion: Our study presented the first evidence that intravenous thrombolysis with 0.65 mg/kg r-tPA may be optimal for Chinese mild-to- moderate stroke. [ABSTRACT FROM AUTHOR]

There has been increasing attention to dose optimization in the development of targeted oncology therapeutics. The current report has analyzed the dose selection approaches for 116 new molecular entities (NMEs) approved for oncology indications by the US FDA from 2010 to August 2021, with the goal to extract learnings about the ways to select the optimal dose. The analysis showed that: (1) the initial label dose was lower than the maximum tolerated dose (MTD) or maximum studied dose (MSD) in Phase 1 for the majority of approved NMEs, and that the MTD approach is no longer the mainstay for dose selection; (2) there was no dose ranging or optimization beyond Phase 1 dose escalation for ~ 80% of the NMEs; (3) integrated dose/exposure-response analyses were commonly used to justify the dose selection; (4) lack of dose optimization led to dose-related PMRs/PMCs in 14% of cases, but 82% of these did not result in change of the initial label dose; and (5) depending on properties of the NME and specific benefit/risk considerations for the target patient population, there could be different dose selection paradigms leading to identification of the appropriate clinical dose. The analysis supports the need to incorporate more robust dose optimization during oncology clinical development, through comparative assessment of benefit/risk of multiple dose levels, over a wide exposure range using therapeutically relevant endpoints and adequate sample size. On the other hand, in certain cases, data from FIP dose escalation may be adequate to support the dose selection. [ABSTRACT FROM AUTHOR]

This study aims to investigate the optimal dose of metformin for controlling the transition to diabetes in patients diagnosed with prediabetes. We systematically searched randomized controlled trials (RCTs) in CNKI, Wanfang, VIP, SinoMed, Scopus, PubMed, Embase, Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) from inception to February 2024. Meta-analysis was conducted using RevMan 5.4 software. We included 25 randomized controlled trials comprising 2437 patients. The results of the meta-analysis revealed that compared to dose groups of 500 mg/d, 850 mg/d, 1000 mg/d, 1500 mg/d, 1700 mg/d, and 2000 mg/d, a dosage of 750 mg/d of metformin significantly reduced the incidence of diabetes in patients (risk ratio [RR] = 0.21, 95 % confidence interval [CI]: 0.11, 0.41; p < 0.00001), lowered Postprandial Blood Glucose (PBG) (mean difference[MD] = −2.60, 95 % CI: −4.34, −0.86; p = 0.003), and promoted the normalization of blood glucose levels (RR = 2.13, 95 % CI: 1.68, 2.71; p < 0.00001). Regarding safety evaluation, no significant differences were identified among the various dose groups. In contrast, the cohort receiving a daily dosage of 750 mg demonstrated the most pronounced decrease in the incidence of adverse reactions. Based on the efficacy and safety evaluation results, our findings suggest that a daily dosage of 750 mg of metformin may represent the optimal dose for controlling the progression from pre-diabetes to diabetes. PROSPERO registration ID: CRD42024538322. • Our study systematically synthesizes existing data to determine the optimal dosage of metformin that effectively prevents the conversion from prediabetes to diabetes. • We provide evidence-based insights into the dose-response relationship of metformin in prediabetic patients, enhancing understanding of its therapeutic effectiveness. [ABSTRACT FROM AUTHOR]

Objective: To analyze the risk factors of refractory mycoplasma pneumoniae pneumonia (RMPP) occurrence in children, and to explore the optimal dose of methylprednisolone treatment. Methods: 183 children with mycoplasma pneumoniae pneumonia (MPP) who were treated in our hospital from July 2018 to August 2021 were selected. According to the degree of illness, the children were divided into general mycoplasma pneumoniae pneumonia (GMPP) group (n=90) and RMPP group (n=93), multivariate Logistic regression equation was constructed to analyze the risk factors of RMPP occurrence in children. All children with RMPP were treated with methylprednisolone on the basis of routine treatment, and they were divided into low-dose group [2 mg/ (kg·d)], medium-dose Group [3 mg/(kg·d)] and high-dose group [4mg/(kg·d)] aaccording to the different dose, with 31 cases in each group. The curative effects, clinical symptoms disappearance time and occurrence of adverse reactions of the three groups were compared. Results: Univariate analysis showed that the fever days in RMPP group were longer than those in GMPP group, the specific constitution, the proportion of children with extrapulmonary complications, the percentage of neutrophils, procalcitonin (PCT), C-reactive protein (CRP), lactate dehydrogenase (LDH) and interleukin-6 (IL-6) were higher than those in GMPP group, and the percentage of lymphocytes was lower than that in GMPP group (P<0.05). Multivariate Logistic regression analysis showed that fever days≥ 10 d, specific constitution, extrapulmonary complications, CRP≥ 24 m/L, LDH≥ 250 iu/L and IL-6≥ 17 pg/mL were the risk factors of RMPP occurrence(P<0.05). The total clinical effective rate of high-dose group was higher than that of medium-dose group and low-dose group (P<0.05), but there was no significant difference in the total clinical response rate between medium-dose group and low-dose group(P>0.05). The cough disappearance time, body temperature recovery normal time, the pulmonary rales disappearance time and the hospital stay in the high-dose group and the medium-dose group were shorter than those in the low-dose group, and the above-mentioned time in the high-dose group was shorter than that in the medium-dose group (P<0.05). There was no significant difference in the incidence of adverse reactions in the three groups(P>0.05). Conclusion: The RMPP occurrence in children is affected by fever days, specific constitution, extrapulmonary complications and the levels of CRP, LDH and other factors. Methylprednisolone 4 mg/ (kg·d) is effective in the treatment of RMPP in children, and which can significantly shorten the time for clinical symptoms to disappear. [ABSTRACT FROM AUTHOR]

Abstract Background Arterial hypotension induced by general anesthesia is commonly identified as a risk factor of morbidity, especially neurological, after cardiac or noncardiac surgery in adults and children. Intraoperative hypotension is observed with sevoflurane anesthesia in children, in particular in neonates, infants younger than 6 months, and preterm babies. Ephedrine is commonly used to treat intraoperative hypotension. It is an attractive therapeutic, due to its dual action on receptors alpha and beta and its possible peripheral intravenous infusion. There are few data in the literature on the use of ephedrine in the context of pediatric anesthesia. The actual recommended dose of ephedrine (0.1 to 0.2 mg/Kg) frequently leads to a therapeutic failure in neonates and infants up to 6 months of age. The use of higher doses would probably lead to a better correction of hypotension in this population. The objective of our project is to determine the optimal dose of ephedrine for the treatment of hypotension after induction of general anesthesia with sevoflurane, in neonates and infants up to 6 months of age. Methods The ephedrine study is a prospective, randomized, open-label, controlled, dose-escalation trial. The dose escalation consists of 6 successive cohorts of 20 subjects. The doses studied are 0.6, 0.8, 1, 1.2, and 1.4 mg/kg. The dose chosen as the reference is 0.1 mg/kg, the actual recommended dose. Neonates and infants younger than 6 months, males and females, including preterm babies who undergo a surgery with general anesthesia inducted with sevoflurane were eligible. Parents of the subject were informed. Then, the subjects were randomized if presenting a decrease in mean blood pressure superior to 20% of their initial mean blood pressure (before induction of anesthesia), despite a vascular filling with sodium chloride 0.9%. The primary outcome is the success of the therapy defined as an mBP superior to 80% of the baseline mBP (prior to anesthesia) within 10 min post ephedrine administration. The subjects were followed-up for 3 days postanesthesia. Discussion This study is the first randomized, controlled trial intending to determine the optimal dose of ephedrine to treat hypotension in neonates and infants below 6 months old. Trial registration ClinicalTrials.gov NCT02384876 . Registered on March 2015.

Introduction. Several diseases affect the Andean blackberry cultivation in Colombia, where anthracnose (Colletotrichum spp.) stands out for generating total losses. Objective. To estimate the doses of N, P, K, and Ca that allow greater tolerance to C. gloeosporioides strain 52 in Andean blackberry seedlings. Materials and methods. The experiment was carried out in 2017, in a greenhouse located in Mosquera in the department of Cundinamarca (Colombia), with seedlings sown in a substrate based on a 3: 1 mixture of peat and rice husks. A randomized complete block design with a central composite arrangement of 25 treatments and 15 seedlings were used per experimental unit. The inoculation of plant material was carried out 53 days after had begun the application of the treatments, with mycelial discs at a concentration of 9.53×104 conidia. The severity percentage (Sev), incubation period (IP), disease development rate (r), plant height (PLH), stem diameter (StD), leaf area (LA), chlorophyll content index (CCI), dry weight of the aerial part, and concentration of nutrients were measured. The analysis of variance with Tukey’s test (p

Simple Summary: Sentinel lymph node biopsy (SLNB) using super magnetic iron oxide (SPIO) and magnetic probes is expected to be a simple and safe method of detecting cancerous lymph nodes without using radioisotopes (RIs). A multicenter trial of SLNB was conducted using a handheld magnetic probe and SPIO (Rizobist®) and its non-inferiority with the conventional RI method. The quantity of iron in SLN was measured to examine the necessary dosage and administration method for sufficient SLN detection in the case of this test. Further, a clinical trial was conducted to determine the possibility of SLNB with a half-dose of SPIO (1.0 mL → 0.5 mL), and the resulting iron volume measured at that time was also examined. This study demonstrates that sufficient iron content reaches SLN even at an SPIO dose of 0.5 mL. This exploratory study compared doses of ferucarbotran, a superparamagnetic iron oxide nanoparticle, in sentinel lymph nodes (SLNs) and quantified the SLN iron load by dose and localization. Eighteen females aged ≥20 years scheduled for an SLN biopsy with node-negative breast cancer were divided into two equal groups and administered either 1 mL or 0.5 mL ferucarbotran. Iron content was evaluated with a handheld magnetometer and quantification device. The average iron content was 42.8 µg (range, 1.3–95.0; 0.15% of the injected dose) and 21.9 µg (1.1–71.0; 0.16%) in the 1-mL and 0.5-mL groups, respectively (p = 0.131). The iron content of the closest SLN compared to the second SLN was 53.0 vs. 10.0 µg (19% of the injected dose) and 34.8 vs. 4.1 µg (11.1%) for the 1-mL and 0.5-mL groups, respectively (p = 0.001 for both). The magnetic field was high in both groups (average 7.30 µT and 6.00 µT in the 1-mL and 0.5-mL groups, respectively) but was not statistically significant (p = 0.918). The magnetic field and iron content were correlated (overall SLNs, p = 0.02; 1-mL, p = 0.014; 0.5-mL, p = 0.010). A 0.5-mL dose was sufficient for SLN identification. Primary and secondary SLNs could be differentiated based on iron content. Handheld magnetometers could be used to assess the SLN iron content. [ABSTRACT FROM AUTHOR]

This study determined the response of methane emission and growth performance of yearling male Boer goats fed a basal diet of Avena sativa hay supplemented with Acacia karroo (sweet thorn) leaf meal. Twelve yearling male Boer goats with initial mean live weights of 23 ± 2 kg were used in a 21-day experiment. The goats were randomly assigned to four dietary treatments, each containing sweet thorn leaf meal at 10, 15, 20 and 30% with Avena sativa hay as a basal diet. The data collected was subjected to analysis of covariance and analysis of variance in a completely randomized design using Statistical Analysis Software. Differences were separated at 5% level of probability. Sweet thorn leaf meal inclusion level had no effect (p > 0.05) on diet intake, methane emission, live weight changes and digestibility. Feed conversion ratio improved linearly with increased Sweet thorn leaf meal inclusion level. The low tannin contents in sweet thorn leaves indicate that these leaves can be safe to use as a source of protein in animal nutrition if used sparingly. Although, sweet thorn leaf meal reduced methane emission, the optimal dose was not determined. Further validation is required to determine sweet thorn inclusion levels for optimal methane production and emission by goats. [ABSTRACT FROM AUTHOR]

BackgroundDexmedetomidine (DEX) administration decreases post-operative nausea and vomiting (PONV), but it is a lack of large-scale retrospective cohort study and is unclear whether there is a dose-relationship and optimal dose for antiemetic effects between DEX and PONV. We performed a large-scale retrospective cohort study to explore the optimal dose of intraoperative DEX for antiemetic effects of PONV.MethodsA total of 5,310 patients aged ≥18 who underwent elective thoracic surgery from January 2016 to March 2020 under total intravenous anesthesia (TIVA) or combined intravenous and inhalation anesthesia in Henan Provincial People's Hospital. Patients were divided into two groups, those who received DEX intraoperatively and those who did not receive DEX. Patients who received DEX after surgery were excluded. Our primary outcomes were the association, the dose-response relationship, and the optimal dose for antiemetic effects between intraoperative DEX and PONV.ResultsAmong the 3,878 patients enrolled, 2,553 patients received DEX and 1,325 patients did not receive DEX. The incidence of PONV in patients who received DEX was 21.3%, and the incidence of PONV in patients who did not receive DEX was 46.5% (P = 0.001). After the matched-pairs cohort consisted of 1,325 patients, the incidence of PONV in patients who received DEX was 23.6%, and the incidence of PONV in patients who did not receive DEX was 46.5% (P = 0.001). We analyzed three different models after propensity matching to validate the stability of the prediction model between intraoperative DEX and PONV. A dose-response relationship between intraoperative DEX and PONV was observed. The optimal dose range of intraoperative DEX for antiemetic effects of PONV is 50–100 μg in elective thoracic surgery.ConclusionsIntraoperative DEX was associated with a decreased incidence of PONV in the large-scale retrospective cohort study. A dose-response relationship between intraoperative DEX and PONV was observed. The optimal dose range of intraoperative DEX for antiemetic effects of PONV is 50–100 μg in elective thoracic surgery.

Background: While tuberculosis (TB) is curable and preventable, the most effective first-line antibiotics cannot kill multi-drug resistant (MDR) Mycobacterium tuberculosis (Mtb). Therefore, effective drugs are needed to combat MDR-TB, especially in children. Our objective was to repurpose cefazolin for MDR-TB treatment in children using principles of pharmacokinetic/pharmacodynamics (PK/PD).Methods: Cefazolin minimum inhibitory concentration (MIC) was identified in 17 clinical Mtb strains, with and without combination of the β-lactamase inhibitor, avibactam. Next, dose-ranging studies were performed using the intracellular hollow fiber model of TB (HFS-TB) to identify the optimal cefazolin exposure. Monte Carlo experiments were then performed in 10,000 children for optimal dose identification based on cumulative fraction of response (CFR) and Mtb susceptibility breakpoint in three age-groups.Results: Avibactam reduced the cefazolin MICs by five tube dilutions. Cefazolin-avibactam demonstrated maximal kill of 4.85 log10 CFU/mL in the intracellular HFS-TB over 28 days. The % time above MIC associated with maximal effect (EC80) was 46.76% (95% confidence interval: 43.04–50.49%) of dosing interval. For 100 mg/kg once or twice daily, the CFR was 8.46 and 61.39% in children

Background: Obsessive-compulsive disorder (OCD) is a common chronic mental disorder with a high disability rate. Serotonin reuptake inhibitors (SRIs), including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, such as clomipramine, are the most common choices for the pharmacological treatment of OCD. Optimizing their use is pivotal in guiding clinical practice of OCD. However, there are few studies on the optimal dose of SRIs and there is controversy about their dose–response relationship and optimal target dose. Therefore, the objective of this study was to summarize the relationship between the dose and effect of SRIs, as well as the optimal dose of SRIs for OCD, as to propose future research directions.Methods: Medline, Embase, Biosis, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and CINAHL were searched for relevant publications, and the search was up to February 22, 2020. We used a one-stage, robust error meta-regression (REMR) model to deal with the correlated dose–response data for SRIs from different studies. Doses of SRIs were converted to fluoxetine equivalents when performing dose–response analysis. Review Manager Program Version 5.3 and STATA software package (version 15.1) were applied to analyze data. The study protocol was registered with PROSPERO (number CRD42020168344).Results: Eleven studies involving 2,322 participants were included in final analysis. For SRIs, the dose–efficacy curve showed a gradual increase trend in the 0–40-mg dose range and then had a decreased trend in doses up to 100 mg fluoxetine equivalent. Dropouts due to adverse effects gradually increased throughout the inspected dose slope. The curve of dose of all-cause dropouts suggested no relationship between them. Sensitivity analysis proved that these results were robust.Conclusion: The systematic review found that the optimal dose for efficacy was about 40mg fluoxetine equivalent. Tolerability decreased with increased doses, and there was no significant correlation between acceptability and doses of SRIs. Therefore, the optimal dose of SRIs needs to consider effectiveness and tolerability.Systematic Review Registration: [PROSPERO], identifier [CRD42020168344].

Background: While tuberculosis (TB) is curable and preventable, the most effective first-line antibiotics cannot kill multi-drug resistant (MDR) Mycobacterium tuberculosis (Mtb). Therefore, effective drugs are needed to combat MDR-TB, especially in children. Our objective was to repurpose cefazolin for MDR-TB treatment in children using principles of pharmacokinetic/pharmacodynamics (PK/PD). Methods: Cefazolin minimum inhibitory concentration (MIC) was identified in 17 clinical Mtb strains, with and without combination of the β-lactamase inhibitor, avibactam. Next, dose-ranging studies were performed using the intracellular hollow fiber model of TB (HFS-TB) to identify the optimal cefazolin exposure. Monte Carlo experiments were then performed in 10,000 children for optimal dose identification based on cumulative fraction of response (CFR) and Mtb susceptibility breakpoint in three age-groups. Results: Avibactam reduced the cefazolin MICs by five tube dilutions. Cefazolin-avibactam demonstrated maximal kill of 4.85 log10 CFU/mL in the intracellular HFS-TB over 28 days. The % time above MIC associated with maximal effect (EC80) was 46.76% (95% confidence interval: 43.04–50.49%) of dosing interval. For 100 mg/kg once or twice daily, the CFR was 8.46 and 61.39% in children <3 years with disseminated TB, 9.70 and 84.07% for 3–5 years-old children, and 17.20 and 76.13% for 12–15 years-old children. The PK/PD-derived susceptibility breakpoint was dose dependent at 1–2 mg/L. Conclusion: Cefazolin-avibactam combination demonstrates efficacy against both drug susceptible and MDR-TB clinical strains in the HFS-TB and could potentially be used to treat children with tuberculosis. Clinical studies are warranted to validate our findings. [ABSTRACT FROM AUTHOR]

Background: Obsessive-compulsive disorder (OCD) is a common chronic mental disorder with a high disability rate. Serotonin reuptake inhibitors (SRIs), including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, such as clomipramine, are the most common choices for the pharmacological treatment of OCD. Optimizing their use is pivotal in guiding clinical practice of OCD. However, there are few studies on the optimal dose of SRIs and there is controversy about their dose–response relationship and optimal target dose. Therefore, the objective of this study was to summarize the relationship between the dose and effect of SRIs, as well as the optimal dose of SRIs for OCD, as to propose future research directions. Methods: Medline, Embase, Biosis, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and CINAHL were searched for relevant publications, and the search was up to February 22, 2020. We used a one-stage, robust error meta-regression (REMR) model to deal with the correlated dose–response data for SRIs from different studies. Doses of SRIs were converted to fluoxetine equivalents when performing dose–response analysis. Review Manager Program Version 5.3 and STATA software package (version 15.1) were applied to analyze data. The study protocol was registered with PROSPERO (number CRD42020168344). Results: Eleven studies involving 2,322 participants were included in final analysis. For SRIs, the dose–efficacy curve showed a gradual increase trend in the 0–40-mg dose range and then had a decreased trend in doses up to 100 mg fluoxetine equivalent. Dropouts due to adverse effects gradually increased throughout the inspected dose slope. The curve of dose of all-cause dropouts suggested no relationship between them. Sensitivity analysis proved that these results were robust. Conclusion: The systematic review found that the optimal dose for efficacy was about 40mg fluoxetine equivalent. Tolerability decreased with increased doses, and there was no significant correlation between acceptability and doses of SRIs. Therefore, the optimal dose of SRIs needs to consider effectiveness and tolerability. Systematic Review Registration: [PROSPERO], identifier [CRD42020168344]. [ABSTRACT FROM AUTHOR]

Il Young Cho1,2 1College of Pharmacy, Ewhawomans University, Seoul, Republic of Korea; 2Pharmaceutical Safety Bureau, Ministry of Food and Drug Safety, Cheongju-si, Republic of KoreaCorrespondence: Il Young ChoPharmaceutical Safety Bureau, Ministry of Food and Drug Safety, 187, Osongsaengmyeong 2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 28159, Republic of KoreaTel +82 43 719 2709Fax +82 43 719 2700Email iycho10@korea.krAbstract: Non-vitamin K oral anticoagulants (NOACs) are increasingly used as alternatives to conventional therapies and have considerable accumulated real-world clinical data in patients with non-valvular atrial fibrillation (NVAF) or venous thromboembolism (VTE). However, it is not easy to make a complete changeover to NOACs in real-world clinical practice because NOACs still have challenges in specific patient populations (eg, Asian patients, NVAF patients presenting with acute coronary syndrome [ACS], dialysis patients with NVAF, patients with cancer-associated VTE, etc.). Clinical data on the optimal dose of NOACs in Asian patients with NVAF are not sufficient. The intensity of NOAC and antiplatelet treatment and the duration of antiplatelet treatment should be adjusted according to the bleeding and thrombotic risk profiles of the individual NVAF patient presenting with ACS. Increased bleeding risk and unclear efficacy of NOACs in dialysis patients with NVAF should be considered when making decisions on whether to give NOACs for these patients. If dialysis patients with NVAF require anticoagulant for stroke prevention, then apixaban could be considered while awaiting more clinical efficacy and safety data. Additional studies are needed to determine the utility of continuing treatment with reduced-dose NOACs for long-term therapy after VTE. We have enough experiences in using NOACs in cancer patients showing the benefit of antithrombotic treatment counterbalanced the bleeding risk; however, some challenges of cancer-associated VTE management exist due to differences in cancer types or chemotherapy regimens and comorbidities. Different dosing regimens among NOACs may impact on medication adherence; thus, individual patient preference should be considered in choosing a particular NOAC. A significant proportion of patients remain on warfarin because of the high price of NOACs and variability in reimbursement coverage. To compensate clinical-evidence and achieve optimal use of NOACs, we should pay attention to the outcomes of ongoing studies and evaluate more real-world data.Keywords: non-valvular atrial fibrillation, venous thromboembolism, risk management plan, optimal dose, drug price, cost-effectiveness

In phase I trials, the main goal is to identify a maximum tolerated dose under an assumption of monotonicity in dose–response relationships. On the other hand, such monotonicity is no longer applied to biologic agents because a different mode of action from that of cytotoxic agents potentially draws unimodal or flat dose–efficacy curves. Therefore, biologic agents require an optimal dose that provides a sufficient efficacy rate under an acceptable toxicity rate instead of a maximum tolerated dose. Many trials incorporate both toxicity and efficacy data, and drugs with a variety of modes of actions are increasingly being developed; thus, optimal dose estimation designs have been receiving increased attention. Although numerous authors have introduced parametric model‐based designs, it is not always appropriate to apply strong assumptions in dose–response relationships. We propose a new design based on a Bayesian optimization framework for identifying optimal doses for biologic agents in phase I/II trials. Our proposed design models dose–response relationships via nonparametric models utilizing a Gaussian process prior, and the uncertainty of estimates is considered in the dose selection process. We compared the operating characteristics of our proposed design against those of three other designs through simulation studies. These include an expansion of Bayesian optimal interval design, the parametric model‐based EffTox design, and the isotonic design. In simulations, our proposed design performed well and provided results that were more stable than those from the other designs, in terms of the accuracy of optimal dose estimations and the percentage of correct recommendations. [ABSTRACT FROM AUTHOR]

Background: Arterial hypotension induced by general anesthesia is commonly identified as a risk factor of morbidity, especially neurological, after cardiac or noncardiac surgery in adults and children. Intraoperative hypotension is observed with sevoflurane anesthesia in children, in particular in neonates, infants younger than 6 months, and preterm babies. Ephedrine is commonly used to treat intraoperative hypotension. It is an attractive therapeutic, due to its dual action on receptors alpha and beta and its possible peripheral intravenous infusion. There are few data in the literature on the use of ephedrine in the context of pediatric anesthesia. The actual recommended dose of ephedrine (0.1 to 0.2 mg/Kg) frequently leads to a therapeutic failure in neonates and infants up to 6 months of age. The use of higher doses would probably lead to a better correction of hypotension in this population. The objective of our project is to determine the optimal dose of ephedrine for the treatment of hypotension after induction of general anesthesia with sevoflurane, in neonates and infants up to 6 months of age.Methods: The ephedrine study is a prospective, randomized, open-label, controlled, dose-escalation trial. The dose escalation consists of 6 successive cohorts of 20 subjects. The doses studied are 0.6, 0.8, 1, 1.2, and 1.4 mg/kg. The dose chosen as the reference is 0.1 mg/kg, the actual recommended dose. Neonates and infants younger than 6 months, males and females, including preterm babies who undergo a surgery with general anesthesia inducted with sevoflurane were eligible. Parents of the subject were informed. Then, the subjects were randomized if presenting a decrease in mean blood pressure superior to 20% of their initial mean blood pressure (before induction of anesthesia), despite a vascular filling with sodium chloride 0.9%. The primary outcome is the success of the therapy defined as an mBP superior to 80% of the baseline mBP (prior to anesthesia) within 10 min post ephedrine administration. The subjects were followed-up for 3 days postanesthesia.Discussion: This study is the first randomized, controlled trial intending to determine the optimal dose of ephedrine to treat hypotension in neonates and infants below 6 months old.Trial Registration: ClinicalTrials.gov NCT02384876 . Registered on March 2015. [ABSTRACT FROM AUTHOR]

Neuroprotection has proven clinically unsuccessful in subarachnoid hemorrhage. We believe that this is because the major component in the early damage pathway, the vascular wall, has not been given the necessary focus. U0126 is a potent inhibitor of vascular phenotypical changes, exemplified by functional endothelin B (ETB) receptor upregulation. The current study aimed to determine the optimal dose of U0126 ex vivo and test the toxicology of this dose in vivo. To find the optimal dose and test a suitable in vivo delivery system, we applied an ex vivo model of blood flow cessation and investigated functional ETB receptor upregulation (using a specific agonist) as the primary endpoint. The secondary endpoint was depolarization-induced contractility assessed by 60 mM K+ stimuli. Furthermore, an in vivo toxicology study was performed on the optimal selected doses. U0126 (10 µM) had a strong effect on the prevention of functional ETB receptor contractility, combined with minimal effect on the depolarization-induced contractility. When cremophor EL was chosen for drug delivery, it had an inhibitory and additive effect (combined with U0126) on the ETB receptor contractility. Hence, 10 µM U0126 in 0.5% cremophor EL seems to be a dose that will be close to the maximal inhibition observed ex vivo on basilar arteries, without exhibiting side effects in the toxicology studies. U0126 and cremophor EL are well tolerated at doses that have effect on ETB receptor upregulation. Cremophor EL has an additional positive effect, preventing functional ETB receptor upregulation, making it suitable as a drug delivery system.

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According to the Federal Law «On Biomedical Cell Products», preclinical trials are an integral part of biomedical cell product (BCP) development. This article describes the basic principles of fulfilling requirements laid down in the Rules for conducting preclinical trials of BCPs. The main objective of preclinical trials is evaluation of efficacy, safety and biodistribution of cell products. Properly justified markers of biological activity must be used for reliable identification of BCP pharmacodynamic action in the host organism. BCP safety assessment must be comprehensive and include identification, characterization and quantitative evaluation of potential local and systemic toxicity, estimation of the onset of toxicity and possibility of its reduction, and the effect of a particular drug dose on the results of toxicity studies. The ultimate goal of preclinical toxicity studies is to obtain data sufficient for making a conclusion on the possibility of conducting clinical trials of BCP and determining associated risks. The key principles of preclinical trials design are a rational approach and justification of all decisions made during the study. The results of preclinical trials that were conducted in compliance with the law, can be included in the BCP dossier and considered during the product authorization by the expert institution of the Ministry of Health.

Post-stroke spasticity impedes patients’ rehabilitation progress. Contradictory evidence has been reported in using Botulinum Neurotoxin type A (BoNT-A) to manage post-stroke lower extremity spasticity (PLES); furthermore, an optimum dose of BoNT-A for PLES has not yet been established. Therefore, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to identify the efficacy and optimal dose of BoNT-A on PLES. "Meta" and "Metafor" packages in R were used to analyze the data. Hedges’ g statistic and random effect model were used to calculate and pool effect sizes. Twelve RCTs met the eligibility criteria. Muscle tone significantly improved in week four, week eight, and maintained to week twelve after BoNT-A injection. Improvements in functional outcomes were found, some inconsistencies among included studies were noticed. Dosage analysis from eight studies using Botox® and three studies using Dysport® indicated that the optimum dose for the commonest pattern of PLES (spastic plantar flexors) is medium-dose (approximately 300U Botox® or 1000 U Dysport®). BoNT-A should be regarded as part of a rehabilitation program for PLES. Furthermore, an optimal rehabilitation program combined with BoNT-A management needs to be established. Further studies should also focus on functional improvement by BoNT-A management in the early stage of stroke.

Neuroprotection has proven clinically unsuccessful in subarachnoid hemorrhage. We believe that this is because the major component in the early damage pathway, the vascular wall, has not been given the necessary focus. U0126 is a potent inhibitor of vascular phenotypical changes, exemplified by functional endothelin B (ETB) receptor upregulation. The current study aimed to determine the optimal dose of U0126 ex vivo and test the toxicology of this dose in vivo. To find the optimal dose and test a suitable in vivo delivery system, we applied an ex vivo model of blood flow cessation and investigated functional ETB receptor upregulation (using a specific agonist) as the primary endpoint. The secondary endpoint was depolarization-induced contractility assessed by 60 mM K+ stimuli. Furthermore, an in vivo toxicology study was performed on the optimal selected doses. U0126 (10 µM) had a strong effect on the prevention of functional ETB receptor contractility, combined with minimal effect on the depolarization-induced contractility. When cremophor EL was chosen for drug delivery, it had an inhibitory and additive effect (combined with U0126) on the ETB receptor contractility. Hence, 10 µM U0126 in 0.5% cremophor EL seems to be a dose that will be close to the maximal inhibition observed ex vivo on basilar arteries, without exhibiting side effects in the toxicology studies. U0126 and cremophor EL are well tolerated at doses that have effect on ETB receptor upregulation. Cremophor EL has an additional positive effect, preventing functional ETB receptor upregulation, making it suitable as a drug delivery system. [ABSTRACT FROM AUTHOR]