The coronavirus disease 2019 (COVID-19) pandemic has stimulated tremendous efforts to develop therapeutic agents that target severe acute respiratory syndrome coronavirus 2 to control viral infection. So far, a few small-molecule antiviral drugs, including nirmatrelvir-ritonavir (Paxlovid), remdesivir, and molnupiravir have been marketed for the treatment of COVID-19. Nirmatrelvir-ritonavir has been recommended by the World Health Organization as an early treatment for outpatients with mild-to-moderate COVID-19. However, the existing treatment options have limitations, and effective treatment strategies that are cost-effective and convenient for tackling COVID-19 are still needed. To date, four domestically developed oral anti-COVID-19 drugs have been granted conditional market approval in China. These drugs include azvudine, simnotrelvir-ritonavir (Xiannuoxin), leritrelvir, and mindeudesivir (VV116). Preclinical and clinical studies have explored the efficacy and tolerability of mindeudesivir and supported its early use in mild-to-moderate COVID-19 cases at high risk for progression. In this review, we discuss the most recent findings regarding the pharmacological mechanism and therapeutic effects focusing on mindeudesivir and other small-molecule antiviral agents for COVID-19. These findings will expand our understanding and highlight the potential widespread application of China's homegrown anti-COVID-19 drugs.
Humans ; Ritonavir/therapeutic use* ; COVID-19 ; Antiviral Agents/therapeutic use* ; China ; Nitriles ; Lactams ; Proline ; Adenosine/analogs & derivatives* ; Leucine

The relationship between androgen and prostate cancer treatment has plagued the field of urologic oncology. To investigate the efficacy and safety of bipolar androgen therapy (BAT) followed by immune checkpoint inhibitor therapy in patients with metastatic castration resistant prostate cancer (mCRPC). In August 2020, Beijing Hospital conducted an investigator-initiated study: Bipolar androgen therapy followed by immune checkpoint inhibitor therapy in metastatic castration resistant prostate cancer. Up to now, the study has included 4 patients who completed the entire cycle of treatment. The mean age of the patients was 74.5 (68 to 82) years old, the mean prostate-specific antigen (PSA) was 20.8 (9.9 to 8.36) μg/L, the mean testosterone was 0.50 (0.00 to 1.81) μg/L, and the Gleason score were 10 and 9, 7, 7 respectively. The pain scale score before treatment was 1.5 (1 to 2). In this study, 4 patients completed the entire cycle of treatment, and the treatment effect of the patients showed great heterogeneity. PSA in case 1 decreased from 24.0 μg/L to 0.47 μg/L, testosterone increased from 0.175 6 μg/L to 2.62 μg/L. PSA in case 2 increased from 9.939 μg/L to 168.536 μg/L, and testosterone increased from 0.0 μg/L increased to 2.85 μg/L. PSA increased from 13.31 μg/L to 39.278 μg/L in case 3, testosterone increased from 0.0 μg/L to 2.54 μg/L. and PSA increased from 36.0 μg/L to 350.2 μg/L in the case 4, testosterone increased from 1.81 μg/L to 3.85 μg/L. Except for one patient who showed significant PSA remission, the PSA levels of the remaining three patients remained high overall. There were no adverse reactions reported in 4 patients. In the follow-up, case 1 continued to use PD-1 monoclonal antibody (median progression free survival time was 10 months). Two patients who had previously been resistant to enzalutamide received enzalutamide again after the whole cycle of treatment, and their PSA decreased again, which indicated that the patient was sensitive to enzalutamide again. BAT had a certain therapeutic effect on mCRPC patients, and the safety was controllable. Its tumor control effect still needed long-term follow-up verification in large-sample clinical trials. BAT has a certain therapeutic effect on mCRPC patient, especially the resensitivity of tumors to enzalutamide can be restored. Immune checkpoint inhibitors may have therapeutic potential in patients with prostate cancer treated with BAT and enzalutamide.
Aged ; Aged, 80 and over ; Androgens/therapeutic use* ; Humans ; Immune Checkpoint Inhibitors ; Male ; Nitriles/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms, Castration-Resistant/drug therapy* ; Testosterone/therapeutic use* ; Treatment Outcome

OBJECTIVE: To evaluate the efficacy and safety of ruxolitinib in patients with polycythemia vera (PV). METHODS: The clinical data of patients with PV treated with ruxolitinib in Peking Union Medical College Hospital from January 1, 2013 to December 31, 2019 were retrospectively analyzed. The starting dose of oral ruxolitinib was 10 mg twice daily and could be increased after 3 months of treatment if hematocrit (HCT) control was not achieved. HCT control was defined as HCT<45% in the absence of phlebotomy. RESULTS: Thirty-three patients (17 males and 16 females) were treated with ruxolitinib at a median age of 50 (21-72) years. JAK2V617F and JAK2exon12 alleles were detected in 31 and 2 patients, respectively. Before treatment, median hemoglobin level was 187 (166-208) g/L, median white blood cell and platelet level was 10.4 (5.0-15.8)×10⁹/L and 457(237-677)×10⁹/L, respectively. Totally 17 patients (51.5%) who were resistant to or intolerant of hydroxyurea were treated with ruxolitinib as second-line therapy, and 16 patients (48.5%) were treated with ruxolitinib as first-line therapy voluntarily. The median time since PV diagnosis to treatment of ruxolitinib was 47 (3-188) months. By December 31, 2019, all the patients continued to receive ruxolitinib. The median duration of ruxolitinib exposure was 19 (2-91) months. Both in the first-line therapy group and second-line therapy group, 15 cases (accounting for 93.8% and 88.2%, respecitvely) achieved HCT control. The median time from start of therapy to HCT control was 2.2 (0.8-11.6) months. One patient (3.0%) had disease progression after HCT control. The most common hematologic adverse events included anemia and thrombocytopenia, according to CTCAE classification, including 1 case of grade 1 anemia (3.0%) and 1 case of grade 2 thrombocytopenia (3.0%). There was no thromboembolic event occurred during the therapy of ruxolitinib. CONCLUSION The remission rate of HCT in PV patients treated with ruxolitinib is high, and adverse reactions are rare. Ruxolitinib is effective in HCT control and generally well tolerated in patients with PV.
Adult ; Aged ; Anemia ; Female ; Hemoglobins/therapeutic use* ; Humans ; Hydroxyurea/therapeutic use* ; Male ; Middle Aged ; Nitriles ; Polycythemia Vera/drug therapy* ; Pyrazoles ; Pyrimidines ; Retrospective Studies ; Thrombocytopenia ; Young Adult

OBJECTIVE: To retrospectively analyze the efficacy and safety of ruxolitinib therapy for children with thalassemia after unrelated or haploidentical stem cell transplantation. METHODS: From March 2020 to March 2021, 22 patients received successfully allogeneic hematopoietic stem cell transplantation in the Zhongshan Hospital of Xiamen University, from +30 to 100 days,those patients received ruxolitinib therapy (2.5 mg, twice daily) and all adverse reactions were observed, include aGVHD, cGVHD, CMV and EBV infection. RESULTS: 22 patients underwent allogeneic stem cell transplantation, 5 patients were diagnosed as aGVHD, 3 patients had grade I－II skin GVHD and 2 patients had grade II intestinal GVHD, those patients were cured. All patients were followed up for more than 21 weeks, 4 cases developed cGVHD, including 3 cases of localized liver GVHD and 1 case of pulmonary GVHD, those were relieved after active treatment. 8 patients had elevated EBV copies (>3×10³/ml), and 3 patients had increased CMV copies, the patients recovered after immunosuppressant and antiviral treatment. There was no CMV infection and EBV related post-transplantant lymphoproliferative disorders(PTLD), and no transplant related deaths. CONCLUSION Ruxolitinib can effectively reduce the incidence and severity of GVHD without affecting the hematopoietic recovery, and improve the survival status of thalassemia children after transplantation.
Antiviral Agents/therapeutic use* ; Child ; Graft vs Host Disease/prevention & control* ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Humans ; Immunosuppressive Agents/therapeutic use* ; Nitriles ; Pyrazoles ; Pyrimidines ; Retrospective Studies ; Thalassemia

Objective: To evaluate the efficacy and tolerability of ruxolitinib combined with prednisone, thalidomide and danazol for treatment of in myelofibrosis (MF). Methods: Patients of MF according to the WHO 2016 criteria, received ruxolitinib (RUX) combined with prednisone, thalidomide and danazol (PTD). The response, changes of blood counts and adverse events were evaluated. Results: Six PMF and one post-ET MF patients were enrolled. Four patients presented JAK2V617F mutation, one CALR mutation, one MPL mutation, one triple-negative. Responses per IWG-MRT criteria were clinical improvement in 5 patients, stable disease in 2 ones, spleen response in 6 ones. All of 7 patients were symptomatic responses, four patients achieved at least 50% improvement from baseline on MPN-SAF TSS. Three patients initially treated with RUX alone, all of 3 patients experienced treatment-associated anemia and thrombocytopenia. Then these 3 patients received RUX combined with PTD, both hemoglobin and platelet increased significantly. Four patients initially treated with RUX combined with PTD. Increased levels of hemoglobin and platelet were seen in all of 7 patients received RUX combined with PTD with maximum increased hemoglobin of 30(18-54) g/L and maximum increased platelets of 116(13-369)×10(9)/L, respectively from baseline. The treatment dose of RUX increased due to improved platelet count in 3 patients. The frequent non-hematologic adverse events grade 1-2 were constipation, abdominal distension, crura edema and increased ALT. Conclusions: RUX combined with PTD for treatment of MF may modulate initial hematologic toxicity observed when RUX alone, and may increase response due to improved levels of hemoglobin or platelet.
Danazol ; Drug Combinations ; Humans ; Nitriles ; Pilot Projects ; Prednisone ; Primary Myelofibrosis/drug therapy* ; Pyrazoles/therapeutic use* ; Pyrimidines ; Thalidomide/therapeutic use* ; Treatment Outcome

Humans ; Leukemia, Myelomonocytic, Chronic/drug therapy* ; Nitriles ; Pyrazoles/therapeutic use* ; Pyrimidines

PROSPER is an international Phase III trial demonstrating the beneficial role of enzalutamide, an androgen receptor antagonist, in prolonging metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer. The trial showed that the median metastasis-free survival was 21.9 months longer for those treated with enzalutamide (36.6 months) compared to those treated with placebo (14.7 months). Enzalutamide also showed prolonged time to PSA progression, PSA response, and time to initiating additional antineoplastic therapy although overall survival is not yet reached. Enzalutamide is the second antiandrogen (next to apalutamide) that has gained the United States Food and Drug Administration (US FDA) label indication for use in the setting of nonmetastatic castration-resistant prostate cancer.
Androgen Antagonists/therapeutic use* ; Antineoplastic Agents/therapeutic use* ; Benzamides ; Humans ; Male ; Nitriles ; Phenylthiohydantoin/therapeutic use* ; Prostatic Neoplasms, Castration-Resistant/drug therapy*

The aim of the present study was to determine whether oncologic outcomes and adverse events associated with active on/off intermittent antiandrogen monotherapy (daily bicalutamide, 50 mg per day) are comparable with those of standard external beam radiation therapy (EBRT) or combined androgen blockade (CAB) therapy in prostate cancers with positive surgical margins after radical prostatectomy. Two hundred twenty-three patients with positive surgical margins post-radical prostatectomy who underwent active surveillance (AS, n = 32), EBRT without hormone therapy (n = 55), intermittent antiandrogen monotherapy without EBRT (IAAM, n = 50), or CAB without EBRT (n = 86), between 2007 and 2014, were reviewed retrospectively. Pathologic outcomes, biochemical recurrence rates, radiological disease progression, and adverse events were collected from medical records. Biochemical recurrence rates, biochemical recurrence-free survival rates, and radiological recurrence were not different between the groups (P = 0.225, 0.896, and 0.284, respectively). Adverse event rates and severities were lower for IAAM compared with EBRT or CAB (both P < 0.05), but were comparable to those for AS (P = 0.591 and 0.990, respectively). Grade ≥3 adverse events were not reported in the IAAM or AS groups. Erectile dysfunction and loss of libido rates were lower in the IAAM group compared with the EBRT and CAB groups (P = 0.032). Gastrointestinal complications were more frequently reported in the EBRT group (P = 0.008). Active on/off IAAM treatment might be an appropriate treatment option for patients with positive surgical margins after radical prostatectomy. Furthermore, regarding oncologic outcomes, IAAM was comparable to standard EBRT but had a milder adverse event profile.
Aged ; Aged, 80 and over ; Androgen Antagonists/adverse effects* ; Anilides/adverse effects* ; Antineoplastic Agents/adverse effects* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Chemotherapy, Adjuvant/adverse effects* ; Disease-Free Survival ; Humans ; Male ; Neoplasm Recurrence, Local/blood* ; Neoplasm, Residual ; Nitriles/adverse effects* ; Prostate-Specific Antigen/blood* ; Prostatectomy ; Prostatic Neoplasms/therapy* ; Radiotherapy, Adjuvant/adverse effects* ; Retrospective Studies ; Tosyl Compounds/adverse effects*

Despite impressive survival benefits with immunotherapy in patients with various solid tumors, the full potential of these agents in prostate cancer has yet to be realized. Sipuleucel-T demonstrated a survival benefit in this population, indicating that prostate cancer is an immunoresponsive disease; however, these results have not been matched by other agents. A large trial with ipilimumab in prostate cancer failed to meet its primary objective, and small trials with PD-1/PD-L1 inhibitors did not yield a significant improvement in overall response. However, several late-stage clinical trials are underway with other vaccines in prostate cancer. Reports of clinical benefit with immunotherapies, particularly when used in combination or a select population, have provided the framework to develop sound clinical trials. Understanding immunogenic modulation, antigen spread, biomarkers, and DNA-repair defects will also help mold future strategies. Through rational patient selection and evidence-based combination approaches, patients with prostate cancer may soon derive durable survival benefits with immunotherapies.
Animals ; Antineoplastic Agents, Immunological/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; B7-H1 Antigen/antagonists & inhibitors* ; Benzamides ; CTLA-4 Antigen/antagonists & inhibitors* ; Cancer Vaccines/therapeutic use* ; Humans ; Immunotherapy ; Ipilimumab/therapeutic use* ; Male ; Nitriles ; Phenylthiohydantoin/analogs & derivatives* ; Programmed Cell Death 1 Receptor/antagonists & inhibitors* ; Prostatic Neoplasms/drug therapy* ; Tissue Extracts/administration & dosage*

Even in the era of novel targeted agents, switching to a second-line nonsteroidal antiandrogen (NSAA) is still widely used in treating metastatic castration-resistant prostate cancer (mCRPC), especially in undeveloped countries. However, whether prior treatment with a second-line NSAA would impact the efficacy of abiraterone acetate (Abi) remains uncertain. In the current study, 87 mCRPC patients treated with Abi were analyzed. Among them, 21 were treated with a second-line NSAA (from bicalutamide to flutamide) before receiving abiraterone, while the remaining 66 received Abi directly. Therapeutic efficacy of Abi was compared between those with and without prior second-line NSAA using Kaplan-Meier curves, log-rank test, and Cox regression models. The therapeutic efficacy of Abi was similar between those with or without the prior switching treatment of flutamide, in terms of either prostate-specific antigen progression-free survival (PSA-PFS, 5.5 vs 5.6 months, P = 0.967), radiographic progression-free survival (rPFS, 12.8 vs 13.4 months, P = 0.508), overall survival (OS, not reached vs 30.6 months, P = 0.606), or PSA-response rate (71.4% [15/21] vs 60.6% [40/66], P = 0.370). This is the first time that the impact of prior switching of treatment to a second-line NSAA on the efficacy of Abi in mCRPC patients has been addressed. Our data support that, use of prior sequential bicalutamide and flutamide does not seem to preclude response to abiraterone, although larger cohort studies and, ideally, a randomized controlled trial are needed. These findings will facilitate doctors' decision-making in the treatment of mCRPC patients, especially for those with previous experience of switching NSAA second-line treatments in the clinic.
Abiraterone Acetate/therapeutic use* ; Aged ; Aged, 80 and over ; Androgen Antagonists/therapeutic use* ; Anilides/therapeutic use* ; Antineoplastic Agents, Hormonal/therapeutic use* ; Disease-Free Survival ; Female ; Flutamide/therapeutic use* ; Humans ; Kaplan-Meier Estimate ; Male ; Nitriles/therapeutic use* ; Nonsteroidal Anti-Androgens/therapeutic use* ; Prostate-Specific Antigen/analysis* ; Prostatic Neoplasms, Castration-Resistant/drug therapy* ; Retrospective Studies ; Survival Analysis ; Tosyl Compounds/therapeutic use* ; Treatment Outcome