Search

Objectives: The aim of this study was to evaluate the capacity of gadopiclenol, a high-relaxivity gadolinium-based contrast agent to detect brain metastases in mice as a function of dose (0.08 mmol/kg or 0.1 mmol/kg) compared with gadobenate at 0.1 mmol/kg., Materials and Methods: Brain metastases were induced by ultrasound-guided intracardiac implantation of 1.10 5 MDA-MB-231Br cells in the left ventricle of 18 anesthetized Balb/c Nude nu/nu female mice. At day 28 ± 3 after cell injection, each mouse received 2 crossover intravenous injections at 24-hour intervals, randomly selected from 2 doses of gadopiclenol (0.08 mmol/kg or 0.1 mmol/kg) and gadobenate (0.1 mmol/kg) with n = 6 mice/group (3 groups). Brain magnetic resonance imaging sessions were performed at 4 weeks on a 2.35 T magnet with a 3-dimensional T1-weighted high-resolution gradient echo sequence, before and after each injection. Images were blindly and randomly analyzed to detect enhancing lesions. Contrast-to-noise ratio between the metastases and the surrounding healthy parenchyma was calculated, based on region-of-interest signal measurements. In 2 animals per group, an early time point was added to the protocol (day 22 ± 3) to evaluate the sensitivity of detection as a function of time. After the last imaging session, the presence and location of whole-brain metastases were confirmed by histology in 4 mice., Results: After gadopiclenol, approximately twice as many metastases were detected compared with gadobenate, regardless of the dose. Contrast-to-noise ratios of the detected metastases were 2.3 and 3.3 times higher with gadopiclenol at 0.08 mmol/kg and 0.1 mmol/kg, respectively, compared with gadobenate at 0.1 mmol/kg ( P < 0.0001). Gadopiclenol at the dose of 0.1 mmol/kg resulted in a 1.4-fold higher contrast compared with gadopiclenol at 0.08 mmol/kg ( P < 0.02). In a subset of mice that were imaged 1 week earlier, 2 metastases were detected with gadopiclenol and not with gadobenate., Conclusions: The high-relaxivity macrocyclic gadolinium-based contrast agent gadopiclenol allowed higher diagnostic performance for detecting brain enhancing metastases in terms of contrast-to-noise ratio and number of detected metastases compared with gadobenate, at both equal (0.1 mmol/kg) dose and 20% lower Gd dose (0.08 mmol/kg). Tumor detection was higher after gadopiclenol at the dose of 0.1 mmol/kg compared with 0.08 mmol/kg., Competing Interests: Conflicts of interest and sources of funding: All authors are Guerbet employee. Banque Publique d'Investissement (France)., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: The aim of the set of studies was to compare gadopiclenol, a new high relaxivity gadolinium (Gd)-based contrast agent (GBCA) to gadobenate dimeglumine in terms of small brain lesion enhancement and Gd retention, including T1 enhancement in the cerebellum., Materials and Methods: In a first study, T1 enhancement at 0.1 mmol/kg body weight (bw) of gadopiclenol or gadobenate dimeglumine was evaluated in a small brain lesions rat model at 2.35 T. The 2 GBCAs were injected in an alternated and cross-over manner separated by an interval of 4.4 ± 1.0 hours (minimum, 3.5 hours; maximum, 6.1 hours; n = 6). In a second study, the passage of the GBCAs into cerebrospinal fluid (CSF) was evaluated by measuring the fourth ventricle T1 enhancement in healthy rats at 4.7 T over 23 minutes after a single intravenous (IV) injection of 1.2 mmol/kg bw of gadopiclenol or gadobenate dimeglumine (n = 6/group). In a third study, Gd retention at 1 month was evaluated in healthy rats who had received 20 IV injections of 1 of the 2 GBCAs (0.6 mmol/kg bw) or a similar volume of saline (n = 10/group) over 5 weeks. T1 enhancement of the deep cerebellar nuclei (DCN) was assessed by T1-weighted magnetic resonance imaging at 2.35 T, performed before the injection and thereafter once a week up to 1 month after the last injection. Elemental Gd levels in central nervous system structures, in muscle and in plasma were determined by inductively coupled plasma mass spectrometry (ICP-MS) 1 month after the last injection., Results: The first study in a small brain lesion rat model showed a ≈2-fold higher number of enhanced voxels in lesions with gadopiclenol compared with gadobenate dimeglumine. T1 enhancement of the fourth ventricle was observed in the first minutes after a single IV injection of gadopiclenol or gadobenate dimeglumine (study 2), resulting, in the case of gadopiclenol, in transient enhancement during the injection period of the repeated administrations study (study 3). In terms of Gd retention, T1 enhancement of the DCN was noted in the gadobenate dimeglumine group during the month after the injection period. No such enhancement of the DCN was observed in the gadopiclenol group. Gadolinium concentrations 1 month after the injection period in the gadopiclenol group were slightly increased in plasma and lower by a factor of 2 to 3 in the CNS structures and muscles, compared with gadobenate dimeglumine., Conclusions: In the small brain lesion rat model, gadopiclenol provides significantly higher enhancement of brain lesions compared with gadobentate dimeglumine at the same dose. After repeated IV injections, as expected for a macrocyclic GBCA, Gd retention is minimalized in the case of gadopiclenol compared with gadobenate dimeglumine, resulting in no T1 hypersignal in the DCN., Competing Interests: Conflicts of interest and sources of funding: All authors are employees of Guerbet., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The aim of this study was to investigate the toxicological profile of gadopiclenol, a new high-relaxivity macrocyclic gadolinium-based contrast agent (GBCA), in renally impaired rats, in comparison with 2 other macrocyclic GBCAs, gadoterate meglumine and gadobutrol, and 1 linear and nonionic GBCA, gadodiamide., Methods: Renal failure was induced by adding 0.75% wt/wt adenine to the diet for 3 weeks. During the second week of adenine-enriched diet, the animals (n = 8/group × 5 groups) received 5 consecutive intravenous injections of GBCA at 2.5 mmol/kg per injection, resulting in a cumulative dose of 12.5 mmol/kg or saline followed by a 3-week treatment-free period after the last injection. The total (elemental) gadolinium (Gd) concentration in different tissues (brain, cerebellum, femoral epiphysis, liver, skin, heart, kidney, spleen, plasma, urine, and feces) was measured by inductively coupled plasma mass spectrometry. Transmission electron microscopy (and electron energy loss spectroscopy analysis of metallic deposits) was used to investigate the presence and localization of Gd deposits in the skin. Relaxometry was used to evaluate the presence of dissociated Gd in the skin, liver, and bone. Skin histopathology was performed to investigate the presence of nephrogenic systemic fibrosis-like lesions., Results: Gadodiamide administrations were associated with high morbidity-mortality but also with macroscopic and microscopic skin lesions in renally impaired rats. No such effects were observed with gadopiclenol, gadoterate, or gadobutrol. Overall, elemental Gd concentrations were significantly higher in gadodiamide-treated rats than in rats treated with the other GBCAs for all tissues except the liver (where no significant difference was found with gadopiclenol) and the kidney and the heart (where statistically similar Gd concentrations were observed for all GBCAs). No plasma biochemical abnormalities were observed with gadopiclenol or the control GBCAs. Histopathology revealed a normal skin structure in the rats treated with gadopiclenol, gadoterate, and gadobutrol, contrary to those treated with gadodiamide. No evidence of Gd deposits on collagen fibers and inclusions in fibroblasts was found with gadopiclenol and its macrocyclic controls, unlike with gadodiamide. Animals of all test groups had Gd-positive lysosomal inclusions in the dermal macrophages. However, the textures differed for the different products (speckled texture for gadodiamide and rough-textured appearance for the 2 tested macrocyclic GBCAs)., Conclusions: No evidence of biochemical toxicity or pathological abnormalities of the skin was observed, and similar to other macrocyclic GBCAs, gadoterate and gadobutrol, tissue retention of Gd was found to be low (except in the liver) in renally impaired rats treated with the new high-relaxivity GBCA gadopiclenol., Competing Interests: Conflicts of interest and sources of funding: All authors are or were employees of Guerbet. This work is part of the Franco-German Project ISEULT and was funded in part by Banque Publique d'Investissement (France) and by Guerbet., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: The main objective of the study was to assess the effect of age on target tissue total gadolinium (Gd) retention after repeated administration of gadodiamide (linear) or gadoterate (macrocyclic) Gd-based contrast agent (GBCA) in rats. The secondary objective was to assess the potential developmental and long-term consequences of GBCA administration during neonatal and juvenile periods., Materials and Methods: A total of 20 equivalent human clinical doses (cumulated dose, 12 mmol Gd/kg) of either gadoterate or gadodiamide were administered concurrently by the intravenous route to healthy adult and juvenile rats. Saline was administered to juvenile rats forming the control group. In juvenile rats, the doses were administered from postnatal day 12, that is, once the blood-brain barrier is functional as in humans after birth. The tests were conducted on 5 juvenile rats per sex and per group and on 3 adult animals per sex and per group. T1-weighted magnetic resonance imaging of the cerebellum was performed at 4.7 T during both the treatment and treatment-free periods. Behavioral tests were performed in juvenile rats. Rats were euthanatized at 11 to 12 weeks (ie, approximately 3 months) after the last administration. Total Gd concentrations were measured in plasma, skin, bone, and brain by inductively coupled plasma mass spectrometry. Cerebellum samples from the juvenile rats were characterized by histopathological examination (including immunohistochemistry for glial fibrillary acidic protein or GFAP, and CD68). Lipofuscin pigments were also studied by fluorescence microscopy. All tests were performed blindly on randomized animals., Results: Transient skin lesions were observed in juvenile rats (5/5 females and 2/4 males) and not in adult rats having received gadodiamide. Persisting (up to completion of the study) T1 hyperintensity in the deep cerebellar nuclei (DCNs) was observed only in gadodiamide-treated rats. Quantitatively, a slightly higher progressive increase in the DCN/brain stem ratio was observed in adult rats compared with juvenile rats, whereas no difference was noted visually. In all tissues, total Gd concentrations were higher (10- to 30-fold higher) in the gadodiamide-treated groups than in the gadoterate groups. No age-related differences were observed except in bone marrow where total Gd concentrations in gadodiamide-treated juvenile rats were higher than those measured in adults and similar to those measured in cortical bone tissue. No significant treatment-related effects were observed in histopathological findings or in development, behavior, and biochemistry parameters. However, in the elevated plus maze test, a trend toward an anxiogenic effect was observed in the gadodiamide group compared with other groups (nonsignificant). Moreover, in the balance beam test, a high number of trials were excluded in the gadodiamide group because rats (mainly males) did not completely cross the beam, which may also reflect an anxiogenic effect., Conclusions: No T1 hyperintensity was observed in the DCN after administration of the macrocyclic GBCA gadoterate regardless of age as opposed to administration of the linear GBCA gadodiamide. Repeated administration of gadodiamide in neonatal and juvenile rats resulted in similar total Gd retention in the skin, brain, and bone to that in adult rats with sex having no effect, whereas Gd distribution in bone marrow was influenced by age. Further studies are required to assess the form of the retained Gd and to investigate the potential risks associated with Gd retention in bone marrow in juvenile animals treated with gadodiamide. Regardless of age, total Gd concentration in the brain and bone was 10- to 30-fold higher after administration of gadodiamide compared with gadoterate.

Purpose: The aim of this study was to investigate, based on in-depth multimodal imaging, the presence of Gd deposits, their ultrastructure, location, and co-location with endogenous elements, in the cerebellum, after repeated administrations of gadolinium-based contrast agents (GBCAs)., Methods: Rats sensitized by subtotal nephrectomy received 20 daily intravenous injections of 0.6 mmol Gd/kg for 5 weeks of commercial forms of either gadoterate, gadobenate or gadodiamide, or saline (n = 2/group). The study was randomized and blinded. Magnetic resonance imaging examination was performed weekly. One month after the last injection, electron microscopy analysis of the deep cerebellar nuclei, the granular layer of cerebellar cortex, and the choroid plexus was performed. Elemental analysis of deposits was carried out by electron energy loss spectroscopy. Secondary ion mass spectroscopy was used for complementary chemical mapping., Results: A T1 hypersignal was evidenced in the deep cerebellar nuclei of rats treated with linear GBCAs, and Gd deposits were identified in all the studied cerebellar structures with gadobenate and gadodiamide (except in the granular layer in gadobenate-treated rats). No such effect was found with the macrocyclic GBCA gadoterate. Most of the Gd deposits revealed a characteristic spheroid "sea urchin-like" morphology, rich in phosphorus, and were localized in the basal lamina of microvessels, in the perivascular Virchow-Robin space, and in the interstitium. Gd was also identified in the glial cells, associated with lipofuscin pigments, for these same groups., Conclusions: Transmission electron microscopy analysis of cerebellums of renally impaired rats repeatedly injected with gadobenate and gadodiamide revealed the presence of Gd. Spheroid Gd depositions consisting of a filamentous meshwork were observed in the wall of microvessels, in perivascular Virchow-Robin space, and in the interstitium. Gd was also found in choroid plexus and was associated with pigments (likely lipofuscin) in glial cells. This is consistent with the involvement of the glymphatic distribution pathway for GBCAs. No insoluble Gd deposits were detected in rats injected with the macrocyclic GBCA gadoterate and controls.

Gadolinium (Gd)-based contrast agents (GBCAs) are pharmaceuticals that have been approved for 30 years and used daily in millions of patients worldwide. Their clinical benefits are indisputable. Recently, unexpected long-term presence of Gd in the brain has been reported by numerous retrospective clinical studies and confirmed in preclinical models particularly after linear GBCA (L-GBCA) compared with macrocyclic GBCA (M-GBCA). Even if no clinical consequences of Gd presence in brain tissue has been demonstrated so far, in-depth investigations on potential toxicological consequences and the fate of Gd in the body remain crucial to potentially adapt the clinical use of GBCAs, as done during the nephrogenic systemic fibrosis crisis. Preclinical models are instrumental in the understanding of the mechanism of action as well as the potential safety consequences. However, such models may be associated with risks of biases, often related to the protocol design. Selection of adequate terminology is also crucial. This review of the literature intends to summarize and critically discuss the main methodological aspects for accurate design and translational character of preclinical studies.

Objectives: This preclinical study was designed to compare gadolinium (Gd) brain uptake after repeated injections of a macrocyclic Gd-based contrast agent (GBCA) (gadoterate meglumine) or 2 linear GBCAs (L-GBCAs) (gadobenate dimeglumine or gadodiamide) on a translational model of moderate renal impairment in rats., Methods: The study was carried out in subtotally nephrectomized rats. Animals received 4 intravenous injections per week of GBCA (gadoterate meglumine, gadobenate dimeglumine, or gadodiamide) for 5 weeks, resulting in a cumulative dose of 12 mmol/kg, followed by a 1-month injection-free period. T1 hyperintensity in the deep cerebellar nuclei (DCNs) was investigated, and brain structures were carefully dissected to determine elemental Gd, iron (Fe), copper (Cu), and zinc (Zn) distribution by mass spectrometry. Urinary excretion of endogenous metals was also investigated soon after GBCA administration and several days later in order to assess a potential transmetalation phenomenon., Results: Unlike gadoterate, repeated injections of L-GBCAs gadobenate and gadodiamide both induced T1 hyperintensity in the DCNs. Fine dissection of cerebral and cerebellar structures demonstrated very low levels or absence of Gd after repeated injections of gadoterate, in contrast to the two L-GBCAs, for which the highest total Gd concentration was demonstrated in the DCNs (Gd concentration in DCNs after 4.5 weeks of injection-free period: 27.1 ± 6.5 nmol/g for gadodiamide [P < 0.01 vs saline and P < 0.05 vs gadoterate]; 12.0 ± 2.6 nmol/g for gadobenate [P < 0.09 vs saline]; compared with 1.4 ± 0.2 nmol/g for gadoterate [ns vs saline]). The distribution of Gd concentration among the various brain structures dissected was also well correlated with the Fe distribution in these structures. No difference in endogenous metal levels in brain structures was observed. However, injection of gadobenate or gadodiamide resulted in an increase in urinary Zn excretion (urinary Zn concentrations: 57.9 ± 20.5 nmol/mL with gadobenate [P < 0.01 vs gadoterate and saline] and 221.6 ± 83.3 nmol/L with gadodiamide [P < 0.0001 vs all other treatments] vs 8.1 ± 2.3 nmol/L with saline and 10.6 ± 4.8 nmol/L with gadoterate])., Conclusions: In a model of renally impaired rats, only traces of gadoterate meglumine were detected in the brain with no T1 hyperintensity of the DCNs, whereas marked Gd retention was observed in almost all brain areas after injections of the L-GBCAs, gadobenate dimeglumine and gadodiamide. Brain structures with higher Gd uptake corresponded to those structures containing more Fe. Urinary Zn excretion was significantly increased after a single injection of L-GBCAs.

Objectives: The purpose of this preclinical study was to investigate whether moderate chronic kidney disease is a factor in potentiating gadolinium (Gd) uptake in the brain., Materials and Methods: A comparative study was performed on renally impaired (subtotal nephrectomy) rats versus rats with normal renal function. The animals received 4 daily injections of 0.6 mmol Gd/kg a week for 5 weeks (cumulative dose of 12 mmol Gd/kg) of gadodiamide or saline solution. The MR signal enhancement in the deep cerebellar nuclei was monitored by weekly magnetic resonance imaging examinations. One week after the final injection, the total Gd concentration was determined by inductively coupled plasma mass spectrometry in different regions of the brain including the cerebellum, plasma, cerebrospinal fluid, parietal bone, and femur., Results: After the administration of gadodiamide, the subtotal nephrectomy group presented a significantly higher T1 signal enhancement in the deep cerebellar nuclei and a major increase in the total Gd concentration in all the studied structures, compared with the normal renal function group receiving the same linear Gd-based contrast agent. Those potentiated animals also showed a pronounced hypersignal in the choroid plexus, still persistent 6 days after the last injection, whereas low concentration of Gd was found in the cerebrospinal fluid (<0.05 μmol/L) at this time point. Plasma Gd concentration was then around 1 μmol/L. Interestingly, plasma Gd was predominantly in a dissociated and soluble form (around 90% of total Gd). Total Gd concentrations in the brain, cerebellum, plasma, and bones correlated with creatinine clearance in both the gadodiamide-treated groups., Conclusions: Renal insufficiency in rats potentiates Gd uptake in the cerebellum, brain, and bones.

Background: Single-agent docetaxel, administered as a 3-weekly infusion has encouraging clinical activity against squamous cell carcinoma of the head and neck (SCCHN). Weekly administration of docetaxel is feasible and showed a favorable toxicity profile in phase I studies. We studied a weekly docetaxel regimen in heavily pretreated patients with head and neck cancer., Patients and Methods: A total of 30 patients with proven metastatic or recurrent SCCHN were treated with docetaxel 36 mg/m weekly for 6 weeks in an 8-week schedule. Dexamethasone 20 mg or methylprednisolone 32 mg was administered 12 and 3 hours before docetaxel. No prophylactic antibiotics or growth factors were given. The primary end point was objective response rate and the secondary end points included time to progression and overall survival., Results: Patients received a median of 6 administrations (range, 1-27). A partial response was documented in 2 patients (6.7%). The disease control rate defined the percentage of patients with responding or stable disease was 33.3%. The median progression-free survival was 7.4 weeks (95% confidence interval, 5.5-9.3 weeks) and the median overall survival was 17.9 weeks (95% confidence interval, 10.1-25.6 weeks). There were no episodes of grade 4 neutropenia, thrombocytopenia, or nonhematological toxicity., Conclusions: Weekly docetaxel at a dose of 36 mg/m has a mild to moderate toxicity profile in SCCHN patients. However, the response rate in predominantly pretreated patients is low and the overall survival is short.

Docetaxel, ifosfamide and cisplatin have proven activity in a broad range of solid tumours and interfere with different phases of the cell cycle. We performed a phase I study with the aim to determine the maximum tolerated dose (MTD) of docetaxel, ifosfamide and cisplatin in patients with solid tumours and to define the safety, dose-limiting toxicity (DLT) and the recommended dose and administration schedule of docetaxel, ifosfamide and cisplatin for further phase II testing. Docetaxel was given by 1-h infusion on day 1, followed by ifosfamide 1000 mg/m(2)/day as a continuous infusion for 5 days. Mesna was added at the same doses to the same infusion bag and was continued for 12 h after the end of ifosfamide. Cisplatin was administered as a 24-h infusion concomitantly with ifosfamide, but in separate infusion bags, either on day 5 (schedule A) or on day 1 (schedule B). Escalation steps were planned only for docetaxel (60, 75, 85 mg/m(2)) and cisplatin (50, 75, 100 mg/m(2)). No intrapatient dose escalation was permitted. Prophylactic ciprofloxacin was used after a protocol amendment was implemented. No prophylactic haematopoietic growth factors were used. Cycles of docetaxel, ifosfamide and cisplatin were given at 3-week intervals. Toxicity was scored according to National Cancer Institute Canada-Common Toxicity Criteria 2. The MTD was defined as the dose at which a DLT was observed in fewer than two of six patients during the first treatment cycle. In total, 85 patients received 309 cycles. Only three escalation steps could be explored and DLTs were observed at each dose level. In total, 32 patients and 49 cycles showed DLTs. Febrile neutropenia occurred in 20 patients (24%). Only two DLTs were nonhaematological (one cerebral infarction and one encephalopathy grade 4). Neutropenia grade 4 lasted for greater than 7 days and/or thrombocytopenia grade 4 was dose limiting in 10 patients. Febrile neutropenia occurred in five of 41 patients (12%) who received prophylactic ciprofloxacin and in 15 of 44 patients (34%) who did not. MTD was reached at level 3 (docetaxel, 75 mg/m(2) and cisplatin, 75 mg/m(2)). With a lower dose of docetaxel (60 mg/m(2)) both schedules A and B were feasible, although, overall, schedule A seemed to be better tolerated. On the basis of this phase I study, the recommended docetaxel, ifosfamide and cisplatin regimen is docetaxel (60 mg/m(2)) on day 1, ifosfamide (1000 mg/m(2)/day) on days 1-5 and cisplatin (75 mg/m(2)) given on day 5. It is associated with substantial haematological toxicity, but this is feasible provided prophylactic antibiotics are used.

The present phase I trial was planned to assess the maximum tolerated dose, the dose-limiting toxicity and the pharmacokinetics of bendamustine hydrochloride in a once every 3 weeks schedule, and to recommend a safe dose for future phase II studies. Included were patients with refractory solid tumors. Bendamustine hydrochloride was administered as a short intravenous infusion over 30 min. The starting dose was defined at 160 mg/m2 and dose escalation used increments of 20 mg/m2. Plasma and urine samples were analyzed using validated high-pressure liquid chromatography/fluorescence assays. Twenty-six patients (14 men, 12 women) were enrolled for the study. At 280 mg/m2, one out of four patients developed a thrombocytopenia grade 4, two experienced grade 3 fatigue and three experienced cardiac toxicity (grade 2). The latter toxicity was considered dose limiting also and further dose escalation was stopped. Plasma pharmacokinetics parameters of bendamustine hydrochloride and its metabolites were assessed in 15 patients. Mean pharmacokinetic parameters of bendamustine hydrochloride were a tmax of 32.3 min, a t1/2 of 37.8 min, a volume of distribution of 14.2 l/m and a clearance of 287.8 ml/min/m2. No dose dependency of bendamustine hydrochloride was observed within the used dose range. The metabolites comprised only 23% of the overall area under the concentration-time curve. The maximum tolerated dose of bendamustine hydrochloride on day 1 q 3 weeks is 280 mg/m2. Fatigue and cardiac toxicity were dose limiting. The plasma pharmacokinetics data of bendamustine and its metabolites were in accordance with previous reports. The recommended dose for future trials is 260 mg/m2 every 3 weeks.