Evaluation of mycophenolic acid exposure in a patient with immune-related hepatotoxicity caused by nivolumab and ipilimumab therapy for malignant melanoma: a case report.

BACKGROUND: Guidelines such as the National Comprehensive Cancer Network recommend mycophenolate mofetil (MMF) for the treatment of severe steroid-refractory immune-related hepatotoxicity. Mycophenolic acid (MPA) is an active form of MMF that suppresses T- and B-lymphocyte proliferation and immune-related adverse events caused by immune checkpoint inhibitors. MPA has a narrow therapeutic range (37-70 µg·h/mL) and overexposure increases the risk of leukopenia in transplantation. However, the optimal use of MMF in oncology has not yet been established; thus, monitoring plasma MPA concentrations is necessary to avoid excessive immunosuppression in oncology practice. CASE PRESENTATION: We evaluated plasma MPA concentration in a 75-year-old man with immune-related hepatotoxicity following nivolumab and ipilimumab combination therapy for malignant melanoma. The patient developed severe hepatotoxicity after immunotherapy, and immunosuppressant therapy with corticosteroids was initiated. The patient then developed steroid-refractory immune-related hepatotoxicity; therefore, MMF (1,000 mg twice daily) was co-administered. Seven days after the administration of MMF, the plasma MPA concentration was measured using an enzyme multiplied immunoassay technique. The area under the plasma concentration-time curve for MPA from 0 to 12 h was 41.0 µg·h/mL, and the same dose of MMF was continued. Grade 2 lymphocytopenia, which could be attributed to MMF, was observed during the administration period. Unfortunately, the patient was infected with SARS-CoV-2 and died from respiratory failure. CONCLUSION: Our patient did not exceed the upper limit of MPA levels as an index of the onset of side effects of kidney transplantation and achieved rapid improvement in liver function. Prompt initiation of MMF after assessment of the steroid effect leads to adequate MPA exposure. Therapeutic drug monitoring should be considered when MMF is administered, to avoid overexposure.

Involvement of Carrier-Mediated Transport at the Blood-Cerebrospinal Fluid Barrier in Spermine Clearance from Rat Brain.

Spermine is the end-product in the polyamine biosynthetic pathway, and its excess accumulation induces neuroexcitatory responses and neurotoxicity. The purpose of this study was to elucidate the involvement of transport systems at the brain barriers in the clearance of spermine. In vivo rat spermine elimination from brain parenchyma across the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCSFB) was assessed by intracerebral and intracerebroventricular administration techniques, respectively. To characterize spermine transport at the BCSFB, a transport study using rat choroid plexus was performed. After the intracerebral microinjection of [3H]spermine, no time-dependent decrease in [3H]spermine in the ipsilateral cerebrum was observed, suggesting the low contribution of the BBB to spermine clearance from the brain. In contrast, the [3H]spermine concentration in the CSF after intracerebroventricular administration was time-dependently decreased with an elimination rate constant of 0.352 min-1, and the elimination clearance of [3H]spermine was 6.6-fold greater than that of [14C]D-mannitol, reflecting bulk flow of the CSF. This [3H]spermine elimination was attenuated by co-administration of unlabeled excess spermine, indicating carrier-mediated elimination of spermine from the CSF. [3H]Spermine transport into the choroid plexus was strongly inhibited by unlabeled spermine, other polyamines (spermidine and putrescine), and organic cation transporter substrates such as corticosterone and 1-methyl-4-phenylpyridinium. However, other substrates/inhibitors for organic cation transporters (decynium-22 and tetraethylammonium) had little effect. Consequently, our study indicates that transporting molecules at the BCSFB, distinct from typical organic cation transporters, are involved in spermine clearance from the CSF.

Effect of number of motor units and muscle fibre type on surface electromyogram.

Reduction in number of motor units (nMU) and fast fibre ratio (FFR) is associated with disease or atrophy when this is rapid. There is a need to study the effect of nMU and FFR to analyse the association with ageing and disease. This study has developed a mathematical model to investigate the relationship between nMU and FFR on surface electromyogram (sEMG) of the biceps muscles. The model has been validated by comparing the simulation outcomes with experiments comparing the sEMG of physically active younger and older cohort. The results show that there is statistically significant difference between the two groups, and the simulation studies closely model the experimental results. This model can be applied to identify the cause of muscle weakness among the elderly due to factors such as muscle dystrophy or preferential loss of type F muscle fibres.

Surface EMG model of the bicep during aging: a preliminary study.

Reduction in the median frequency and the amplitude of surface electromyogram (sEMG) has been observed among older subjects compared with the younger cohort. These changes in sEMG have been associated with a reduction in the number of muscle fibers and a drop in the ratio of type II muscle fibers. However, the details of this association are not known. This paper has experimentally determined the difference between the magnitude and spectrum of sEMG of the younger and older cohorts, and estimated the changes to the muscle by populating a lifelike model with the experimental data. Experiments were conducted on subjects belonging to younger (20-28 years) and older (61-69) age groups. From the simulated results, it is shown that experimental sEMG signals are matched by the model representing the older cohort with a substantially reduced number of motor units compared to the younger people. In the model, the best match with experimental results was observed when the ratio of the bicep motor units between the older and the younger subjects was 0.5. The results also indicate a substantial reduction in the ratio of fast fibers, from 0.45 in the younger cohort to 0.11 in the older cohort.