Neuropathy-Inducing Effects of Eribulin Mesylate Versus Paclitaxel in Mice with Preexisting Neuropathy

Eribulin mesylate (E7389, INN:eribulin mesilate Halaven^®) is a non-taxane microtubule dynamics inhibitor currently in clinical use for advanced breast cancer. Other microtubule-targeting agents for breast cancer, including paclitaxel and ixabepilone, display a common treatment dose-limiting toxicity of peripheral neuropathy (PN). In an earlier study, we found eribulin mesylate had a lower propensity to induce PN in mice than either paclitaxel or ixabepilone. In the current study, we compared additional PN induced by paclitaxel versus eribulin mesylate when administered to mice with preexisting paclitaxel-induced PN. Initially, paclitaxel at 0.75 × its maximum tolerated dose (MTD; 22.5 mg/kg) was given on a Q2Dx3 regimen for 2 weeks. The second chemotherapy was 0.5 MTD eribulin mesylate (0.875 mg/kg) or paclitaxel (15 mg/kg) on a similar regimen, starting 2 weeks after the first. Initial paclitaxel treatment produced significant decreases in caudal nerve conduction velocity (NCV; averaging 19.5 ± 1 and 22.2 ± 1.3 %, p < 0.001) and amplitude (averaging 53.2 ± 2.6 and 72.4 ± 2.1 %, p < 0.001) versus vehicle when measured 24 h or 2 weeks after dosing cessation, respectively. Additional 0.5 MTD paclitaxel further reduced caudal NCV and amplitude relative to immediately before initiation of the second regimen (by 11 ± 2.1 and 59.2 ± 5 %, p < 0.01, respectively). In contrast, 0.5 MTD eribulin mesylate caused no further decrease in caudal NCV. In conclusion, unlike additional paclitaxel treatment, eribulin mesylate administered to mice with preexisting paclitaxel-induced PN had limited additional deleterious effects at 6 weeks. These preclinical data suggest that eribulin mesylate may have reduced tendency to exacerbate preexisting paclitaxel-induced PN in clinical settings.     

Assessment of in vivo fetal growth and placental vascular function in a novel intrauterine growth restriction model of progressive uterine artery occlusion in guinea pigs

Key points

• Intrauterine growth restriction (IUGR) is associated with short‐ and long‐term detrimental cardiometabolic effects.
• Mice and rats are commonly used to assess IUGR, but differences in placental and fetal developmental physiology relative to those in humans highlight the need for alternative small animal IUGR models.
• We developed a guinea pig IUGR model by gradual occlusion of uterine arteries by ameroid constrictor implantation. In this model, reduced uterine blood flow was associated with IUGR, allowing in vivo assessment of fetal growth trajectory and umbilico‐placental vascular function in conscious animals.
• The intervention induces placental vascular dysfunction and remodelling, as well as altered fetal abdominal growth resulting in an asymmetric IUGR and preserved brain growth.

Abstract

Intra‐uterine growth restriction (IUGR) is associated with short and long‐term metabolic and cardiovascular alterations. Mice and rats have been extensively used to study the effects of IUGR, but there are notable differences in fetal and placental physiology relative to those of humans that argue for alternative animal models. This study proposes that gradual occlusion of uterine arteries from mid‐gestation in pregnant guinea pigs produces a novel model to better assess human IUGR. Fetal biometry and in vivo placental vascular function were followed by sonography and Doppler of control pregnant guinea pigs and sows submitted to surgical placement of ameroid constrictors in both uterine arteries (IUGR) at mid‐gestation (35 days). The ameroid constrictors induced a reduction in the fetal abdominal circumference growth rate (0.205 cm day⁻¹) compared to control (0.241 cm day⁻¹, P < 0.001) without affecting biparietal diameter growth. Umbilical artery pulsatility and resistance indexes at 10 and 20 days after surgery were significantly higher in IUGR animals than controls (P < 0.01). These effects were associated with a decrease in the relative luminal area of placental chorionic arteries (21.3 ± 2.2% vs. 33.2 ± 2.7%, P < 0.01) in IUGR sows at near term. Uterine artery intervention reduced fetal (∼30%), placental (∼20%) and liver (∼50%) weights (P < 0.05), with an increased brain to liver ratio (P < 0.001) relative to the control group. These data demonstrate that the ameroid constrictor implantations in uterine arteries in pregnant guinea pigs lead to placental vascular dysfunction and altered fetal growth that induces asymmetric IUGR.     

Increase in the effectiveness of somatodendritic 5-HT-1A receptors in a rat model of tardive dyskinesia

The present study concerns responsiveness of pre- and postsynaptic 5-hydroxytryptamine (5-HT)-1A receptors in a rat model of tardive dyskinesia (TD). Vacuous chewing movements (VCMs) in rats are widely accepted as an animal model of TD. Results show that haloperidol injected at a dose of 1 mg/kg twice a day for 5 weeks elicited VCMs, which increased in a time dependent manner following the drug administration for 3-5 weeks. Tolerance was produced in motor coordination during the potentiation of VCMs. Exploratory activity in an open field and in an activity box decreased in haloperidol treated animals. The effects of 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT; 0.5 mg/kg) were monitored 48-h after withdrawal from repeated administration of haloperidol. 8-OH-DPAT-induced locomotion was greater in haloperidol treated rats. 5-HT synthesis increased in haloperidol treated animals, while 8-OH-DPAT-induced decreases of 5-HT synthesis were greater in repeated haloperidol than repeated saline injected animals. The results suggest that an increase in the effectiveness of somatodendritic 5-HT-1A receptors may decrease the inhibitory influence of 5-HT on the activity of dopaminergic neurons to precipitate VCMs. The 5-HT-1A agonist may help to alleviate neuroleptic-induced TD.     

COVID‐19 in a high‐risk dual heart and kidney transplant recipient

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is rapidly infecting people worldwide, resulting in the infectious disease coronavirus disease 19 (COVID‐19) that has been declared a pandemic. Much remains unknown about COVID‐19, including its effects on solid organ transplant (SOT) recipients. Given their immunosuppressed state, SOT recipients are presumed to be at high risk of complications with viral infections such as SARS‐CoV‐2. Limited case reports in single SOT recipients, however, have not suggested a particularly severe course in this population. In this report, we present a dual‐organ (heart/kidney) transplant recipient who was found to have COVID‐19 and, despite the presence of a number of risk factors for poor outcomes, had a relatively mild clinical course.     

Does the hip positioning matter for oblique lumbar interbody fusion approach? A morphometric study

European Spine Journal - To evaluate whether left hip positioning widened the access corridor using oblique lateral interbody fusion (OLIF) approach during right lateral decubitus (RLD). Ten...     

Livedo reticularis associated with dapsone therapy in a patient with chronic urticaria

Dapsone is a drug commonly used in the treatment of various dermatological diseases. Here, we report the case of a 45-year-old female prescribed dapsone for chronic urticaria after which she developed extensive livedo reticularis in the limbs, abdomen, and trunk. The use of dapsone may be associated with a plethora of adverse effects including rash but livedo reticularis has been very rarely reported. Emphasis should be laid on the possible drug etiology in any patient who develops new signs and symptoms while on medications, even if it may not be supported by enough literature.KEY WORDS: Chronic urticaria, Dapsone, livedo reticularis, rash     

M-mode and cross-sectional echocardiographic features of flail aortic leaflets

The echocardiographic features in seven patients with flail aortic leaflets are described and are correlated with the anatomical appearance of the valve at the time of surgery or autopsy. M-mode echocardiography showed coarse and "shaggy" diastolic echoes within the aortic root and thickening of the aortic leaflets during systole in all patients. Six patients had coarse and "shaggy" diastolic echoes within the left ventricular outflow tract in continuity with similar echoes within the aortic root. Cross-sectional echocardiography in three patients revealed a cord-like mass prolapsing into the left ventricular outflow tract during diastole. Three of the patients had no vegetations at the time of surgery. Both modes of echocardiography are of value in demonstrating abnormal echoes prolapsing into the left ventricular outflow tract, characteristic of flail aortic leaflets that can occur in the presence or absence of vegetations.