From the Clinical to the Bench: Exploring the Insulin Modulation Effects of Tacrolimus and Belatacept.

Calcineurin inhibitors (CNIs) are critical in preventing rejection posttransplantation but pose an increased risk of post-transplant diabetes (PTD). Recent studies show that late conversion from CNIs to belatacept, a costimulation blocker, improves HbA1c in kidney transplant recipients with PTD or de novo diabetes. This study investigates whether the observed effects on PTD stem solely from CNI withdrawal or if belatacept influences PTD independently. The study assessed the impact of tacrolimus and belatacept on insulin secretion in MIN6 cells (a beta cell line) and rat islets. Tacrolimus and belatacept were administered to the cells and islets, followed by assessments of cell viability and insulin secretion. Tacrolimus impaired insulin secretion without affecting cell viability, while belatacept showed no detrimental effects on either parameter. These findings support clinical observations of improved HbA1c upon switching from tacrolimus to belatacept. Belatacept holds promise in islet or pancreas transplantation, particularly in patients with unstable diabetes. Successful cases of islet transplantation treated with belatacept without severe hypoglycemia highlight its potential in managing PTD. Further research is needed to fully understand the metabolic changes accompanying the transition from CNIs to belatacept. Preserving insulin secretion emerges as a promising avenue for investigation in this context.

Diabetes in spotlight: current knowledge and perspectives of photobiomodulation utilization.

Introduction: Diabetes is a global health concern characterized by chronic hyperglycemia resulting from insulinopenia and/or insulin resistance. The rising prevalence of diabetes and its associated complications (ulcers, periodontitis, healing of bone defect, neuropathy, retinopathy, cardiopathy and nephropathy) necessitate innovative therapeutic approaches. Photobiomodulation (PBM), involves exposing tissues and cells to low-energy light radiation, leading to biological effects, largely via mitochondrial activation. Methods: This review evaluates preclinical and clinical studies exploring the potential of PBM in diabetes and its complications, as well all clinical trials, both planned and completed, available on ClinicalTrials database. Results: This review highlights the variability in PBM parameters across studies, hindering consensus on optimal protocols. Standardization of treatment parameters and rigorous clinical trials are needed to unlock PBM's full therapeutic potential. 87 clinical trials were identified that investigated PBM in diabetes mellitus (with 5,837 patients planned to be treated with PBM). Clinical trials assessing PBM effects on diabetic neuropathy revealed pain reduction and potential quality of life improvement. Studies focusing on wound healing indicated encouraging results, with PBM enhancing angiogenesis, fibroblast proliferation, and collagen density. PBM's impact on diabetic retinopathy remains inconclusive however, requiring further investigation. In glycemic control, PBM exhibits positive effects on metabolic parameters, including glucose tolerance and insulin resistance. Conclusion: Clinical studies have reported PBM-induced reductions in fasting and postprandial glycemia without an increased hypoglycemic risk. This impact of PBM may be related to its effects on the beta cells and islets in the pancreas. Notwithstanding challenges, PBM emerges as a promising adjunctive therapy for managing diabetic neuropathy, wound healing, and glycemic control. Further investigation into its impact on diabetic retinopathy and muscle recovery is warranted.

Evaluation of drug cost savings related to clinical trials from the perspective of a university hospital.

OBJECTIVES: Clinical trials are an opportunity for patients to access innovative therapy, but patient inclusion in clinical trials can also result in cost savings for hospitals. Our objective was to evaluate the economic impact of clinical trials drug cost savings in a French academic institution from the perspectives of both the French Health Insurance (FHI) and hospitals. METHODS: A retrospective, observational, cost saving analysis was performed on all the clinical trials initiated in our university hospital between 2015 and 2020. Only trials involving an investigational medicinal product were considered. Drug cost savings were defined as the best standard of care, defined in the protocol, whose cost was covered by a sponsor. RESULTS: Of the 646 trials undertaken during the 6 years analysed, 21% (212/646) led to cost savings, mostly driven by the industrial sponsor (92%, €6 984 283/€7 591 612) for a total of €7 591 612 (91% from the FHI's perspective (€6 959 115/€7 591 612)). Oncology trials generated 79.1% (€6 004 966/€7 591 612) of global cost savings, mostly driven by onco-haematology (33.1%, €1 983 146/€6 004 966), onco-pneumology (29.2%, €1 754 333/€6 004 966) and onco-dermatology (23.5%, €1 409 553/€6 004 966) followed by hepatogastroenterology trials (6.9%, €413 113/€6 004 966). Of the 162 drugs, the top 15 generated 75.3% (€5 715 479/€7 591 612) of savings and were grouped together: 12 antineoplastic agents (six per os and six intravenous) and three per os antiviral for hepatitis C. CONCLUSIONS: With ever-changing prices and new innovative treatments, such cost avoidance must be regularly evaluated. We provided objective evidence that clinical trials could achieve potential cost savings for the FHI and hospitals, in addition to the potential benefit to patients of having access to innovative investigational medicinal products.

Sotorasib associated with tacrolimus and everolimus: A significant drug interaction in lung transplant patients.

The management of immunosuppressors in solid organ transplantation requires pharmacological therapeutic monitoring with regular adaptation of the dosage to the residual level. An obvious cause of these fluctuations is drug interactions, particularly for mTOR inhibitors and anti-calcineurin drugs, which are highly metabolized by cytochromes P450. A 72-year-old lung transplanted man, treated by tacrolimus and everolimus in the long term, had his residual immunosuppressor levels unbalanced by the introduction of sotorasib, which is used for metastatic pulmonary adenocarcinoma. This imbalance is explained by the fact that sotorasib is an inducer of CYP3A4 and an inhibitor of PGP, but the strength of the interaction has never been studied. This will have required a threefold increase in dosages and weekly monitoring before satisfactory residual levels were achieved.

Atypical Evolution of Secondary Hemolytic Uremic Syndrome Defined as Paraneoplastic Syndrome under Eculizumab and Palbociclib Therapies.

Thrombotic microangiopathy (TMA) is most of the time caused by thrombotic thrombocytopenic purpura or hemolytic uremic syndrome. A 60-year-old female was diagnosed in 2014 with mammary breast adenocarcinoma treated by several-line therapy: mastectomy, docetaxel, cyclophosphamide, radiotherapy, doxorubicine, and capecitabine. By mid-November, the patient was admitted to the hospital with regenerative, mechanical, and hemolytic anemia, schistocytes at 3%, and thrombopenia (99 G/L), associated with high blood transfusion requirement. After 9 sessions of plasmapheresis, there was no significant improvement in the biological parameters, nor after 2 cycles of paclitaxel. The patient was then treated with eculizumab during 4 weeks, with a slight reduction in blood requirement, and simultaneously with palbociclib. Since being treated with palpociclib, she had a great reduction in blood requirement and a good clinical condition. To conclude, we reported an initial moderate improvement of paraneoplasm-related TMA syndrome under eculizumab therapy with a slight reduction in red blood cell requirement; however, palbociclib therapy achieved a very good response with a dramatic reduction in red blood cell requirement.