Nirmatrelvir increases blood tacrolimus concentration in COVID-19 patients as determined by UHPLC-MS/MS method.

OBJECTIVE: Transplant recipients have a higher risk of SARS-CoV-2 infection owing to the use of immunosuppressive drugs like tacrolimus (FK506). FK506 and nirmatrelvir (NMV) (an anti-SARS-CoV-2 drug) are metabolized by cytochrome P450 3A4 and may have potential drug-drug interactions. It is important to determine the effect of NMV on FK506 concentrations. PATIENTS AND METHODS: Following protein precipitation from blood, FK506 and its internal standard (FK506-13C,2d4) were detected by ultra-high performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS). Total 22 blood samples (valley concentrations) from two coronavirus disease 2019 (COVID-19) patients were collected and analyzed for FK506 concentrations. RESULTS: Blood levels of FK506 (0.5-100 ng/mL) showed good linearity. The UHPLC-MS/MS method was validated with intra- and inter-batch accuracies of 104.55-107.85%, and 99.52-108.01%, respectively, and precisions of < 15%. Mean blood FK506 concentration was 12.01 ng/mL (range, 3.15-33.1 ng/mL). Five-day co-administration with NMV increased the FK506 concentrations from 3.15 ng/mL to 33.1 ng/mL, returning to 3.36 ng/mL after a 9-day-washout. CONCLUSIONS: We developed a simple quantification method for therapeutic drug monitoring of FK506 in patients with COVID-19 using UHPLC-MS/MS with protein precipitation. We found that NMV increased FK506 blood concentration 10-fold. Therefore, it is necessary to re-consider co-administration of FK506 with NMV.

[Analysis of liver function injury associated with 2019-nCoV Omicron mutant strains].

Objective: To investigate the clinical features and influencing factors of liver function injury in patients with 2019-nCoV/SARS-CoV-2 Omicron mutant strains. Methods: 1 183 confirmed imported cases of SARS-CoV-2 who were admitted at Shanghai Public Health Clinical Center (affiliated to Fudan University) from July 1, 2021 to January 15, 2022 were collected. Clinical data, viral genotyping and laboratory test results were collected to retrospectively analyze the basic condition and clinical characteristics of liver function injury. Statistical analysis was performed using t-test or Wilcoxon rank-sum test, χ2 test or Fisher's exact test, Pearson correlation test and logistic regression analysis. Results: 125 (10.6%) cases had raised baseline ALT level and 60 (5.1%) cases had abnormal baseline AST level. Among them, 33 cases (2.8%) had received hepatoprotective drugs. Liver function injury was generally mild in SARS-CoV-2 infection and minimal in Omicron mutant strains. Leukocyte count was increased in patients with raised alanine aminotransferase (ALT) [(6.96±1.78)×109/L vs. (6.41±1.96)×109/L, P=0.005 2], CT scan showed the proportion of liver hypodensity was significantly increased (2.4% vs. 0.3%, P=0.018 0). High-sensitivity C-reactive protein [(7.83±22.36) mg/L vs. (2.68±6.21) mg/L, P=0.007 8] and D-dimer [(0.34±0.39) µg/ml vs. (0.31±0.75) µg/ml, P=0.047 5] levels were higher in patients with raised AST than normal group. 26 cases had normal liver function at hospital admission; however, abnormal liver function was occurred during the course of the disease. Another 8 patients had abnormal liver function at hospital admission, and reduced liver function further during the course of treatment. Recovery time and length of hospital stay was significantly affected in patients with worsened liver function. Baseline body mass index value [odds ratio (OR)]=1.80, P=0.047), non-Omicron strains (OR=12.63, P=0.046), D-dimer (OR=2.36, P=0.047) and interleukin-6 levels (OR=1.03, P=0.009), and those who used glucocorticoids and/or ulinastatin after hospital admission (OR=6.89, P=0.034) had a higher risk of worsening liver function. Conclusions: Liver dysfunction could be observed among COVID-19 patients. Patients infected with omicron variant generally showed mild liver injury. Dynamic monitoring of liver function is necessary, especially among those with baseline elevated IL-6, D-Dimer level and use of antiinflammation medication during treatment.

[Effects of angiotensin converting enzyme inhibitor/angiotensin receptor blocker on clinical characteristics of coronavirus disease 2019 patients with hypertension].

Objective: To analyze the effects of angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) on coronavirus disease 2019 (COVID-19) patients with hypertension, and to provide an evidence for selecting antihypertensive drugs in those patients. Methods: Clinical data were retrospectively analyzed in 58 COVID-19 patients with hypertension admitted to Shanghai Public Health Clinical Center from January 20 to February 22, 2020, including epidemiological history, clinical manifestations, laboratory findings, chest CT and outcome. Patients were divided into ACEI/ARB group and non-ACEI/ARB group. Results: Twenty-six patients were in ACEI/ARB group and the other 32 patients in non-ACEI/ARB group, with median age 64.0 (49.5, 72.0) years and 64.0 (57.0, 68.8) years respectively. The median time to onset was 5(3, 8) days in ACEI/ARB group and 4 (3, 7) days in non-ACEI/ARB group, the proportion of patients with severe or critical illness was 19.2% and 15.6% respectively. The main clinical symptoms in two groups were fever (80.8% vs. 84.4%) and cough (23.1% vs. 31.3%). The following parameters were comparable including lymphocyte counts, C-reactive protein, lactate dehydrogenase, D-dimer, bilateral involvement in chest CT (76.9% vs. 71.9%), worsening of COVID-19 (15.4% vs. 9.4%), favorable outcome (92.3% vs. 96.9%) between ACEI/ARB group and non-ACEI/ARB group respectively (all P>0.05). However, compared with non-ACEI/ARB group, serum creatinine [80.49 (68.72, 95.30) µmol/L vs. 71.29 (50.98, 76.98) µmol/L, P=0.007] was higher significantly in ACEI/ARB group. Conclusions: ACEI/ARB drugs have no significant effects on baseline clinical parameters (serum creatine and myoglobin excluded) , outcome, and prognosis of COVID-19 patients with hypertension. Antihypertensive drugs are not suggested to adjust in those patients, but the potential impairment of renal function as elevation of serum creatinine should be paid attention in patients administrating ACEI/ARB drugs.

[Risks factors for death among COVID-19 patients combined with hypertension, coronary heart disease or diabetes].

OBJECTIVE: The pathogenesis of myocardial injury upon corona virus disease 2019 (COVID-19) infection remain unknown,evidence of impact on outcome is insufficient, therefore, we aim to investigate the risk factors for death among COVID-19 patients combined with hypertension, coronary heart disease or diabetes in this study. METHODS: This was a single-centered, retrospective, observational study. Patients of Sino-French Eco-City section of Tongji Hospital, Wuhan, China attended by Peking University Supporting Medical Team and admitted from Jan. 29, 2020 to Mar. 20, 2020 were included. The positive nucleic acid of COVID-19 virus and combination with hypertension, coronary heart disease or diabetes were in the standard. We collected the clinical data and laboratory examination results of the eligible patients to evaluate the related factors of death. RESULTS: In the study, 94 COVID-19 patients enrolled were divided into the group of death (13 cases) and the group of survivors (81 cases), the average age was 66.7 years. Compared with the survival group, the death group had faster basal heart rate(103.2 beats/min vs. 88.4 beats /min, P=0.004), shortness of breath(29.0 beats /min vs. 20.0 beats /min, P<0.001), higher neutrophil count(9.2×109/L vs. 3.8×109/L, P<0.001), lower lymphocyte count(0.5×109/L vs. 1.1×109/L, P<0.001), creatine kinase MB(CK-MB, 3.2 µg/L vs. 0.8 µg/L, P<0.001), high sensitivity cardiac troponin Ⅰ(hs-cTnⅠ, 217.2 ng/L vs. 4.9 ng/L, P<0.001), N-terminal pro brain natriuretic peptide(NT-proBNP; 945.0 µg/L vs. 154.0 µg/L, P<0.001), inflammatory factor ferritin(770.2 µg/L vs. 622.8 µg/L , P=0.050), interleukin-2 recepter(IL-2R, 1 586.0 U/mL vs. 694.0 U/mL, P<0.001), interleukin-6(IL-6, 82.3 ng/L vs. 13.0 ng/L, P<0.001), interleukin-10(IL-10, 9.8 ng/L vs. 5.0 ng/L, P<0.001)were higher than those in the survival group. Univariate logistic regression analysis showed that the risk factors for death were old age, low non oxygen saturation, low lymphocyte count, myocardial injury, abnormal increase of IL 2R, IL-6, and IL-10. Multivariate regression showed that old age (OR=1.11, 95%CI=1.03-1.19, P=0.026), low non oxygen saturation(OR=0.85, 95%CI=0.72-0.99, P=0.041), and abnormal increase of IL-10(＞9.1 ng/L, OR=101.93, 95%CI=4.74-2190.71, P=0.003)were independent risk factors for COVID-19 patients combined with hypertension, coronary heart disease or diabetes. CONCLUSION: In COVID-19 patients combined with hypertension, coronary heart disease or diabetes, the risk factors for death were old age, low non oxygen saturation, low lymphocyte count, myocardial injury, and abnormal increase of IL-2R, IL-6, and IL-10. Old age, low non oxygen saturation and abnormal increase of IL-10 were independent risk factors.

[Analysis of baseline liver biochemical parameters in 324 cases with novel coronavirus pneumonia in Shanghai area].

Objective: To summarize the clinical characteristics and liver biochemical parameters of 324 cases admitted with novel coronavirus pneumonia in Shanghai area. Methods: Clinical data and baseline liver biochemical parameters of 324 cases with novel coronavirus pneumonia admitted to the Shanghai Public Health Clinical Center from January 20, 2020 to February 24, 2020 were retrospectively analyzed. Patients were divided into two groups based on the status of illness: mild type (mild and typical) and severe type (severe and critical).The differences in clinical data and baseline liver biochemical parameters of the two groups were described and compared. The t-test and Wilcoxon rank-sum test were used for measurement data. The enumeration data were expressed by frequency and rate, and chi-square test was used. Results: Of the 324 cases with novel coronavirus pneumonia, 26 were severe cases (8%), with median onset of 5 days, 20 cases were HBsAg positive (6.2%), and 70 cases (21.6%) with fatty liver, diagnosed with X-ray computed tomography. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), total bilirubin (TBil), albumin(ALB) and international normalized ratio (INR) of 324 cases at baseline were 27.86 ± 20.02 U/L, 29.33 ± 21.02 U/L, 59.93 ± 18.96 U / L, 39.00 ± 54.44 U/L, 9.46 ± 4.58 µmol / L, 40.64 ± 4.13 g / L and 1.02 ± 0.10. Of which, ALT was > than the upper limit of normal (> ULN), accounting for 15.7% (51/324). ALT and AST > ULN, accounting for 10.5% (34/324). ALP > ULN, accounting for 1.2% (4/324). ALP and GGT > ULN, accounting for 0.9% (3/324). INR > ULN was lowest, accounting for 0.6% (2/324). There were no statistically significant differences (P > 0.05) in ALT [(21.5 vs. 26) U / L, P = 0.093], ALP [(57 vs.59) U/L, P = 0.674], and GGT [(24 vs.28) U/L, P = 0.101] between the severe group and the mild group. There were statistically significant differences in AST (23 U/L vs. 34 U/L, P < 0.01), TBil (10.75 vs. 8.05 µmol / L, P < 0.01), ALB (35.79 ± 4.75 vs. 41.07 ± 3.80 g/L, P < 0.01), and INR (1.00 vs. 1.04, P < 0.01). Conclusion: The baseline liver biochemical parameters of 324 cases with novel coronavirus pneumonia in Shanghai area was comparatively lower and the liverinjury degree was mild, and the bile duct cell damage was rare.