Our previous survey on first-in-human trials (FIHT) of monoclonal antibodies (mAbs) showed that, due to their limited toxicity, the recommended phase II dose (RP2D) was only tentatively defined.
We ...identified, by MEDLINE search, articles on single-agent trials of mAbs with an FIHT included in our previous survey. For each mAb, we examined tested dose(s) and dose selection rationale in non-FIHTs (NFIHTs). We also assessed the correlation between doses tested in the registration trials (RTs) of all FDA-approved mAbs and the corresponding FIHT results.
In the 37 dose-escalation NFIHTs, the RP2D indication was still poorly defined. In phase II-III NFIHTs (n=103 on 37 mAbs), the FIHT RP2D was the only dose tested for five mAbs. For 16 mAbs, only doses different from the FIHT RP2D or the maximum administered dose (MAD) were tested and the dose selection rationale infrequently indicated. In the 60 RTs on 27 FDA-approved mAbs with available FIHT, the FIHT RP2D was tested only for two mAbs, and RT doses were much lower than the FIHT MAD.
The rationale beyond dose selection in phase II and III trials of mAbs is often unclear in published articles and not based on FIHT data.
We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development ...strategies for this class of compounds.
We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013.
A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion.
This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined.
In this paper, a simple approach for the fabrication of a nanosensor with silver nanoparticles electrodeposited on carbon graphite at room temperature is presented, able to detect traces of ...metronidazole molecules. X-ray diffraction and scanning electron microscopy analysis show the formation of silver nanoparticles on the carbon. The particle size and conductivity of the modified electrodes were determined using scanning electron microscopy and electrochemical impedance spectroscopy. The catalytic properties and high adsorption affinity of the antiprotozoal metronidazole using silver deposited on the electrode with potential ranging from −1400 to 300 mV were studied. The electro catalytic activities towards the reduction of metronidazole were strongly affected by the experimental parameters of silver electrodeposition that were optimized (scan rate 5 mV/s, scan potential range 300 to −1400 mV, number of cycles 1 and silver concentration 5 × 10
−3
M in the electrolyte solution and pH = 2 of the supporting electrolyte). The optimized size of the silver nanoparticles is of the order of d
mean
= 180 nm. The current intensity of the detection peak using Ag-NPs@CPE electrode increased linearly with increasing metronidazole concentration in the range of 1 × 10
−6
to 1.0 × 10
−3
M (
R
2
= 0.9956), with a low detection and quantification limit such as 2.06 × 10
−7
M and 6.88 × 10
−7
M respectively. Finally, the AgNPs@CPE nanosensor demonstrated its efficiency for the detection of metronidazole in commercial milk and tap water with a recovery rate higher than 90%.
Graphical abstract
The Zn–Al–Cl Layered Double Hydroxide (Zn–Al–Cl LDH) was synthesized at constant pH by coprecipitation method and then used as an adsorbent for the removal of a reactive azo dye Remazol Red 23 ...(RR-23). The structural and morphological properties of the synthesized Zn–Al–Cl LDH were determined using X-ray diffraction (XRD), Fourier Transform Infrared spectroscopy (FTIR), Brunauer–Emmett–Teller surface area, Scanning Electron Microscopy, Energy Dispersive X-ray Spectroscopy, Thermogravimetry Analysis, and Differential Thermal Analysis, and the determination of the point of zero charge pH
pzc
. The adsorption characteristics were studied by optimizing different parameters such as solution pH, contact time, and initial dye concentration. The maximum adsorption capacity was obtained in the pH ranging from 4 to 7. XRD and FTIR results of Zn–Al–Cl LDH before and after adsorption showed that the removal of the dye is due to its adsorption on the surface of the LDH and that there is no intercalation of the dye since no change in the basal spacing was observed. The kinetic data obtained were examined using the pseudo-first and pseudo-second-order equations. The equilibrium adsorption data were studied using the Freundlich and Langmuir models. The adsorption behavior of Zn–Al–Cl LDH fits perfectly the Langmuir isotherm and the pseudo second-order kinetic model. Thermodynamic studies revealed that the RR-23 dye adsorption on Zn–Al–Cl LDH was exothermic and governed by a physisorption
(
Δ
ads
H
0
<
0
)
, spontaneous
(
Δ
ads
G
0
<
0
)
and increased the randomness
(
Δ
ads
S
0
>
0
)
in the adsorbent/adsorbate system. The regeneration study was also conducted in three cycles with 98, 91, and 74% removal efficiency of RR-23.
Graphical abstract
A novel electrochemical sensor based on eggshell and silver (ES@Ag nanocomposite) was developed for the detection of the antibiotic drug Ornidazole (ORD). The nanocomposite was prepared via in situ ...reduction of silver nanoparticles (AgNPs), and then, the nanocomposite was used as a modifier of carbon paste electrode (CPE) to obtain the electrochemical sensor (ES@Ag/CPE). Crystallinity, composition, and morphology of the synthesized nanocomposite were determined using various analytical methods such as X-ray diffraction (XRD), Scanning Electron Microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). The electrochemical performance of the prepared ES@Ag/CPE was evaluated using Cyclic Voltammetry (CV), Electrochemical Impedance Spectroscopy (EIS) and Square Wave Voltammetry (SWV). The ES@Ag/CPE showed an excellent electrochemical performance and a high electrocatalytic activity toward the detection of ORD. Also, the cathode current from the ORD reduction at ES@Ag/CPE showed a linear response with a concentration in the range of 1000–0.1 μM. Moreover, the values of detection limit (LOD) and quantification limit (LOQ) were low (0.025 µM and 0.085 µM, respectively). The prepared sensor exhibited excellent reproducibility and stability.
Graphical abstract
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