Nirmatrelvir/ritonavir treatment of patients with COVID-19 taking tacrolimus: case series describing the results of drug-drug interactions.

Nirmatrelvir/ritonavir is a novel drug combination that is authorized by the Food and Drug Administration for the treatment of coronavirus disease 2019 (COVID-19). Ritonavir is a cytochrome P450 3A inhibitor and a P-glycoprotein inhibitor that increases the plasma concentration of tacrolimus and other medications. We describe the cases of two patients treated with nirmatrelvir/ritonavir: a patient who had undergone kidney transplantation and another with a history of hematopoietic stem cell transplantation. Toxic concentrations of tacrolimus were induced in both. This case series highlights the risk associated with the concomitant administration of tacrolimus and nirmatrelvir/ritonavir.

Biomimetic exosomal vesicles loaded with siRNA improves antitumor immune responses by inhibiting the secretion of tumor-derived exosome PD-L1.

Tumor-derived exosome PD-L1 exhaustsTcells and permits tumor cells to evade immune surveillance; thus, the inhibition of ExoPD-L1 secretion can significantly enhance the clinical efficacy of PD-L1 antibody. In this study, we combined exosome membrane, apoA1 and phospholipid into biomimetic exosome vesicles (apoA1-bExo) which were then incubated with cholesterol modified siRNA to generate apoA1-bExo containing siRNA (apoA1-bExo/siRNA). Thepreparedvesicleswere uniformandsphericalin size and could be loaded effectively with siRNA to protect from nuclease degradation. Compared with bExo/siRNA, apoA1-bExo/siRNA showed stronger tumor targeting, tissue permeability, intracellular accumulation efficiency and antitumor efficiency. A portion of apoA1-bExo/siRNA transport siRNA occurred through the endosome-Golgi-ER pathway similar to bExo/siRNA, but mostly occurred directly through selective uptake pathways mediated by the SR-B1 receptor. apoA1-bExo/siRNA successfully achieved silencing efficiency at the transcription and protein levels (96.78 % and 94.07 %, respectively) and reduced the secretion of ExoPD-L1 from HepG2 cells to 15.92 % of that in the PBS group, thus enhancing the killing activity of co-cultured T cells on HepG2 cells. In addition, relevant pharmacodynamic indices were positively correlated with delivery efficiency and the modification of apoA1 could significantly enhance the intracellular accumulation of siRNA, thus exhibiting stronger activity than bExo/siRNA. Moreover, in addition to curing mice of their implanted tumors, blocking ExoPD-L1 secretion in combination with αPD-1 promoted the infiltration of durable antitumor hCD8+ T cells and hCD45+ T cells into tumor in a immune system-tumor dual humanized mice.

Ileus induced by the combination of vinca alkaloids and posaconazole in a patient with acute lymphoblastic leukemia: a case report and literature review.

Vinca alkaloid (VA)-induced ileus, a rare but severe autonomic neuropathy, can be enhanced by concomitant use of antifungal triazole agents. We herein present a case of VA-induced ileus in a 17-year-old girl who was diagnosed with B-cell acute lymphoblastic leukemia. On day 1, the patient received cyclophosphamide, vincristine, and methylprednisolone. On day 2, she began treatment with posaconazole oral suspension at 200 mg three times daily for prophylaxis against invasive fungal infection. On day 5, she began induction therapy consisting of vindesine, methylprednisolone, daunorubicin, and cyclophosphamide. The patient developed severe abdominal pain with marked constipation on day 11 and was diagnosed with incomplete ileus. After switching the antifungal agent to micafungin, performing gastrointestinal decompression, administering parenteral nutrition, and omitting the fourth dose of vindesine, the ileus symptoms were relieved. This case emphasizes the potential interaction between VAs and posaconazole. We also herein present a review of the literature on ileus caused by the combination of VAs and antifungal triazole agents. In clinical practice, physicians and pharmacists should be aware of the possibility of ileus caused by the use of VAs in combination with posaconazole. It is important to reduce complications during chemotherapy to improve patients' prognosis.

A case of toxic epidermal necrolysis associated with lenvatinib and sintilimab therapy for intrahepatic cholangiocarcinoma.

Lenvatinib is used as the first-line treatment for intrahepatic cholangiocarcinoma. Sintilimab is a programmed cell death receptor-1 (PD-1) antibody used in the treatment of solid tumors. We present the case of a 78-year-old man with fatal toxic epidermal necrolysis (TEN) associated with the use of sintilimab followed by lenvatinib. This patient, who presented with intrahepatic cholangiocarcinoma, first received immunotherapy with sintilimab according to the standard schedule of 200 mg every 3 weeks. The patient began to receive 8 mg of lenvatinib daily 1 day after sintilimab therapy was initiated. Multiple erythematous papules and blisters appeared on the patient's face and trunk and gradually spread to his arms and legs, and the lesions extensively involved >30% of the body surface area 18 days after lenvatinib initiation. The patient stopped taking lenvatinib on the next day. The skin rash quickly progressed over 1 week to a tender, exfoliative dermatosis. Despite treatment with high-dose steroids and intravenous immunoglobulin, the patient died. To the best of our knowledge, this is the first case of TEN associated with the use of sintilimab followed by lenvatinib. Early diagnosis and treatment of possibly fatal TEN reaction secondary to anti-PD-1 antibody therapy followed by lenvatinib is necessary.