Using part of the initial analgesic dose as the epidural test dose did not delay the onset of labor analgesia: a randomized controlled clinical trial.

BACKGROUND: Epidural test dose for labor analgesia is controversial and varies widely in clinical practice. It is currently unclear whether using a portion of the initial dose for analgesia as the test dose delays the onset time of analgesia, compared to the traditional test dose. METHODS: One hundred and twenty-six parturients who chose epidural analgesia during labor were randomly assigned to two groups. The first dose in group L was 3 ml 1.5% lidocaine, and in the RF group was 10 ml 0.1% ropivacaine combined with 2 µg/ml fentanyl. After 3 min of observation, both groups received 8 ml 0.1% ropivacaine combined with 2 µg/ml fentanyl. The onset time of analgesia, motor and sensory blockade level, numerical pain rating scale, patient satisfaction score, and side effects were recorded. RESULTS: The onset time of analgesia in group RF was similar to that in group L (group RF vs group L, 7.0 [5.0-9.0] minutes vs 8.0 [5.0-11.0] minutes, p = 0.197). The incidence of foot numbness (group RF vs group L, 34.9% vs 57.1%, p = 0.020) and foot warming (group RF vs group L, 15.9% vs 47.6%, p < 0.001) in group RF was significantly lower than that in group L. There was no difference between the two groups on other outcomes. CONCLUSIONS: Compared with 1.5% lidocaine 3 ml, 0.1% ropivacaine 10 ml combined with 2 µg/ml fentanyl as an epidural test dose did not delay the onset of labor analgesia, and the side effects were slightly reduced. CLINICAL TRIAL REGISTRATION: http://www.chictr.org.cn (ChiCTR2100043071).

The median effective concentration of ropivacaine for ultrasound-guided caudal block in children: a dose-finding study.

PURPOSE: To determine the 50% minimum effective concentration (MEC50) and the 95% effective concentration (MEC95) of ropivacaine for ultrasound-guided caudal block during hypospadias repair surgery of pediatric patients. METHODS: Children were enrolled with the American Society of Anesthesiologists (ASA) physical status I-II undergoing elective hypospadias repair surgery. Children were grouped into two age groups: toddlerhood (1-3 years old) and preschool (3-6 years old). We measured The MEC50 using Dixon's up-and-down method. The first children received the caudal block with 1.0 mL/kg of 0.15% ropivacaine. We determined each subsequent patient's concentration based on the previous patient's response and adjusted the concentration in intervals of 0.015%. Meanwhile, the probit regression analysis obtains 95% effective concentration (MEC95). In addition, we recorded the general condition, adverse events, and postoperative pain of each child. RESULTS: 46 children undergoing elective hypospadias repair surgery were included in this study, 22 in the toddlerhood group and 24 in the preschool group. Of the total number of patients, the caudal block was successful in 25 (54%) and failed in 21 (46%). The MEC50 of 1 ml/kg ropivacaine was 0.102% (95% CI 0.099%, 0.138%) in the toddlerhood group and 0.129% (95% CI 0.124%, 0.138%) in the preschool group. The MEC95 of 1 ml/kg ropivacaine was 0.148% (95% CI 0.131%, 0.149%) in the toddlerhood group and 0.162% (95% CI 0.134%, 0.164%) in the preschool group. Our results showed that ropivacaine concentration was statistically different between preschool children and toddlers (P < 0.001). None of the adverse events occurred. CONCLUSIONS: This study showed that children in the preschool group required higher concentrations of ropivacaine than children in the toddler group during ultrasound-guided sacral block combined with non-intubated general anesthesia. At the same time, this method of anesthesia is safe and effective for children undergoing surgery for hypospadias.

Favipiravir for symptomatic COVID-19: A nationwide observational cohort study.

INTRODUCTION: Favipiravir, an antiviral agent with activity against SARS-CoV-2, was made available to hospitals in Japan for off-label use among COVID-19 patients between 2020 and 2021. METHODS: A nationwide observational cohort study was conducted on patients who received favipiravir as part of clinical care between February 2020 and December 2021. Information was collected on demographics, comorbidities, severity of illness, use of favipiravir and other medications targeting COVID-19, adverse events, clinical status at 7 and 14 days and clinical outcome one month after admission to the hospital. RESULTS: A total of 17,508 hospitalized patients who received favipiravir were registered from 884 hospitals. In terms of demographics, 55.9% were age ≥60 years, and 62.3% were male. At least one of the four surveyed comorbidities was present in 45.5% of the patients. The rates of clinical improvement at 7 and 14 days were 72.4％ and 87.5%, 61.4% and 76.6%, and 45.4% and 59.5% for mild, moderate, and severe diseases, respectively. The case fatality rates within a month from hospitalization were 3.3%, 12.6%, and 29.1% for mild, moderate, and severe diseases, respectively. Significant correlations were observed between death and advanced age, male sex, moderate or severe disease, diabetes, cardiovascular diseases, and immunosuppression. Commonly reported adverse events included uric acid level increase or hyperuricemia (16.8%), liver function abnormalities (6.9%), and rash (1.0%). CONCLUSIONS: Favipiravir was well tolerated among COVID-19 patients. The study provides insights into the use of this agent at hospitals across Japan in the early phase of the pandemic.

Safety and efficacy of combined ropivacaine and sufentanil compared with ropivacaine for cesarean sections: A systematic review and meta-analysis.

Cesarean sections are the most common operations in the United States and one of the most common worldwide. Using the lowest possible dose of anesthetic that provides painless delivery with the lowest adverse events is a major concern. We investigated the efficacy and safety of combined ropivacaine and sufentanil by pooling data from relevant studies. We searched PubMed, Web of sciences, Scopus, and Cochrane Library until the end of December 2021 and included all records with data about combined ropivacaine and sufentanil. We used Review Manager to pool data as a mean difference for continuous outcomes or risk ratio for dichotomous outcomes with a 95% confidence interval. Methodological quality was appraised using version one of the Cochrane risks of bias tool. Seven Randomized clinical trials with a total sample size of 730 women were included; the mean age of enrolled parturients ranged from 28 to 35 years. We found that combined sufentanil and ropivacaine were significantly associated with decreased risk of being aware and nervous during CS (presented by Sedation level 1) (RR: 0.05, 95%CI [0.01,0.33], P=0.002), decreased risk of shivering (RR=0.29, 95%CI [0.19,0.44], P<0.00001), nausea (RR=0.62, 95%CI [0.41, 0.92], P=0.02), and vomiting (RR=0.27, 95% CI [0.12, 0.61], P=0.002). However, combined sufentanil and ropivacaine slightly were associated with late-onset of sensory blockade (MD=0.41, 95%CI [0.13, 0.68], P=0.004) and less motor blockade of leg flexion at hip joint presented by Bromage Scale 0 (RR=7.15 95%CI [2.71, 18.86], P<0.0001). Combined ropivacaine and sufentanil were associated with a reduction in visceral pain and lower risks of hypotension, shivering, nausea, and vomiting, compared to isolated ropivacaine, with no difference regarding the incidence of bradycardia. Although Combined ropivacaine and sufentanil were associated with a higher risk of pruritus, the incidence of pruritus was reportedly proportionate with the used dose of sufentanil. However, combined ropivacaine and sufentanil may slightly delay the onset of the sensory blockade to pinprick at T10 with less motor blockade but with a smaller probability for women to be aware and nervous during CS.

Effects of topical prostaglandin therapy on corneal layers thickness in primary open-angle glaucoma patients using anterior segment optical coherence tomography.

PURPOSE: To evaluate the effects of latanoprost, bimatoprost, and travoprost eye drops and their preservatives on each corneal layer thickness in patients with primary open-angle glaucoma (POAG). METHODS: We retrospectively analyzed 79 eyes of 79 patients with POAG who were receiving prostaglandin therapy. Patients were divided into three subgroups according to monotherapy with latanoprost, bimatoprost, and travoprost during a mean of 43.14 ± 19.12 months follow-up period. In addition, the central corneal epithelial thickness (CET), central corneal stromal thickness (CST), and total central corneal thickness (CCT) were measured by anterior segment optical coherence tomography (AS-OCT) at baseline and every six months after treatment initiation at each visit between 9 and 12 o'clock in the morning. Furthermore, intraocular pressure (IOP) was measured with Goldmann applanation tonometry (GAT) after AS-OCT measurements at each visit. RESULTS: All three groups were not significantly different in age, gender, follow-up period, and mean intraocular pressure values (p > 0.05 for all). The reduction of CCT in the latanoprost, bimatoprost, and travoprost groups was 6.53 ± 3.17, 18.59 ± 8.42, and 10.1 ± 1.13 µm, respectively. The decrease in CST values was 4.65 ± 1.54, 15.84 ± 7.47, 9.69 ± 1.45 µm, and CET values were 1.88 ± 1.66, 2.75 ± 0.73, 0.41 ± 0.54 µm in all groups, respectively. A statistically significant thinning was observed in all corneal layers (p < 0.05) except the CST values in the latanoprost group and CET values in the travoprost group. However, no significant difference was found in the average reduction of CET, CST, and CCT values among the three groups (p > 0.05). CONCLUSION: Topical treatment with latanoprost, bimatoprost, and travoprost affects each layer of the cornea separately according to the active and protective substances contained in these eye drops. On the other hand, the thinning effect on the corneal layers was similar in these three drugs because there was no significant difference between the three groups in the total amount of thinning of the corneal layers during the follow-up period.

Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria.

BACKGROUND: Induction of delta aminolevulinic acid synthase 1 ( ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations in patients with acute intermittent porphyria, a rare inherited disease of heme biosynthesis. Givosiran is an investigational RNA interference therapeutic agent that inhibits hepatic ALAS1 synthesis. METHODS: We conducted a phase 1 trial of givosiran in patients with acute intermittent porphyria. In part A of the trial, patients without recent porphyria attacks (i.e., no attacks in the 6 months before baseline) were randomly assigned to receive a single subcutaneous injection of one of five ascending doses of givosiran (0.035, 0.10, 0.35, 1.0, or 2.5 mg per kilogram of body weight) or placebo. In part B, patients without recent attacks were randomly assigned to receive once-monthly injections of one of two doses of givosiran (0.35 or 1.0 mg per kilogram) or placebo (total of two injections 28 days apart). In part C, patients who had recurrent attacks were randomly assigned to receive injections of one of two doses of givosiran (2.5 or 5.0 mg per kilogram) or placebo once monthly (total of four injections) or once quarterly (total of two injections) during a 12-week period, starting on day 0. Safety, pharmacokinetic, pharmacodynamic, and exploratory efficacy outcomes were evaluated. RESULTS: A total of 23 patients in parts A and B and 17 patients in part C underwent randomization. Common adverse events included nasopharyngitis, abdominal pain, and diarrhea. Serious adverse events occurred in 6 patients who received givosiran in parts A through C combined. In part C, all 6 patients who were assigned to receive once-monthly injections of givosiran had sustained reductions in ALAS1 messenger RNA (mRNA), delta aminolevulinic acid, and porphobilinogen levels to near normal. These reductions were associated with a 79% lower mean annualized attack rate than that observed with placebo (exploratory efficacy end point). CONCLUSIONS: Once-monthly injections of givosiran in patients who had recurrent porphyria attacks resulted in mainly low-grade adverse events, reductions in induced ALAS1 mRNA levels, nearly normalized levels of the neurotoxic intermediates delta aminolevulinic acid and porphobilinogen, and a lower attack rate than that observed with placebo. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02452372 .).

Pharmacokinetic characterization of favipiravir in patients with COVID-19.

This prospective observational study describes the pharmacokinetic characteristics of favipiravir in adult patients hospitalized for mild to moderate COVID-19 with a positive RT-PCR test. Favipiravir was administered for 5 days, with a loading dose of 3200 mg and a maintenance dose of 1200 mg/day. Serial blood samples were collected on Day 2 and Day 4 of the therapy. Laboratory findings of the patients (n = 21) and in-hospital mortality were recorded. Favipiravir concentrations exhibited substantial variability and a significant decrease during the treatment of COVID-19. The median favipiravir trough concentration (C0-trough ) on Day 2 was 21.26 (interquartile range [IQR], 8.37-30.78) µg/mL, whereas it decreased significantly to 1.61 (IQR, 0.00-6.41) µg/mL on Day 4, the area under the concentration-time curve decreased by 68.5%. Day 2 C0-trough of female patients was higher than male patients. Our findings indicate that favipiravir concentrations show significant variability during the treatment of COVID-19 and therapeutic drug monitoring may be necessary to maintain targeted concentrations.

Postoperative Analgesic Efficacy and Safety of Ropivacaine Plus Diprospan for Preemptive Scalp Infiltration in Patients Undergoing Craniotomy: A Prospective Randomized Controlled Trial.

BACKGROUND: Preemptive injection of local anesthetics can prevent postoperative pain at the incision site, but the analgesic effect is insufficient and is maintained only for a relatively short period of time. Diprospan is a combination of quick-acting betamethasone sodium phosphate and long-acting betamethasone dipropionate. Whether Diprospan as an adjuvant to local anesthetic can achieve postcraniotomy pain relief has not been studied yet. METHODS: This is a prospective, single-center, blinded, randomized, controlled clinical study, which included patients ages 18 and 64 years, with American Society of Anaesthesiologists (ASA) physical statuses of I to III, scheduled for elective supratentorial craniotomy. We screened patients for enrollment from September 3, 2019, to August 15, 2020. The final follow-up was completed on February 15, 2021. Eligible patients were randomly assigned to either the Diprospan group, who received incision-site infiltration of 0.5% ropivacaine plus Diprospan (n = 48), or the control group, who received 0.5% ropivacaine alone (n = 48), with a distribution ratio of 1:1. Primary outcome was the cumulative sufentanil (µg) consumption through patient-controlled analgesia (PCA) within 48 hours after surgery. Primary analysis was performed based on the intention-to-treat (ITT) principle. RESULTS: Baseline characteristics were not significantly different between the 2 groups ( P > .05). In the Diprospan group, the cumulative sufentanil consumption through PCA was 5 (0-16) µg within 48 hours postoperatively, which was significantly lower than that in the control group (38 [30.5-46] µg; P < .001). CONCLUSIONS: Infiltration of ropivacaine and Diprospan can achieve satisfactory postoperative pain relief after craniotomy; it is a simple, easy, and safe technique, worth clinical promotion.

Favipiravir-induced cutaneous adverse reactions in patients infected with COVID-19.

Favipiravir (FVP) has been used for treatment of COVID-19 in many countries. We analysed the incidence of FVP-induced cutaneous adverse reactions (CARs) in patients infected with COVID-19 who were hospitalized at Bamrasnaradura Infectious Diseases Institute, a principal centre of emerging infectious disease in Thailand, and who presented with cutaneous eruption following FVP prescription. We identified five cases of FVP-induced CARs: two patients with maculopapular rash, two with urticarial rash, and one with Stevens-Johnson syndrome. The median interval between FVP treatment and rash occurrence was 7 days and the mean duration of the rash was 5 days. This report highlights that FVP can induce CARs, particularly eruptions, in COVID-19-infected patients. Clinicians should be aware of this possible drug-related allergy, and it should be excluded as a cause of rash during FVP treatment of COVID-19.

Potentiation of endocannabinoids and other lipid amides prevents hyperalgesia and inflammation in a pre-clinical model of migraine.

Targeting fatty acid amide hydrolase (FAAH) is a promising therapeutic strategy to combat certain forms of pain, including migraine headache. FAAH inhibitors, such as the O-biphenyl-3-yl carbamate URB597, have been shown to produce anti-hyperalgesic effects in animal models of migraine. The objective of this study was to investigate the behavioral and biochemical effects of compounds ARN14633 and ARN14280, two URB597 analogs with improved solubility and bioavailability, in a migraine-specific rat model in which trigeminal hyperalgesia is induced by nitroglycerin (NTG) administration. ARN14633 (1 mg/kg, i.p.) and ARN14280 (3 mg/kg, i.p.) were administered to adult male Sprague-Dawley rats 3 hours after NTG injection. One hour after the administration of either compound, rats were subjected to the orofacial formalin test. ARN14633 and ARN14280 attenuated NTG-induced nocifensive behavior and reduced transcription of genes encoding neuronal nitric oxide synthase, pain mediators peptides (calcitonin gene-related peptide, substance P) and pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta and 6) in the trigeminal ganglion, cervical spinal cord and medulla. Finally, both compounds strongly elevated levels of endocannabinoids and/or other FAAH substrates in cervical spinal cord and medulla, and, to a lesser extent, in the trigeminal ganglia. The results indicate that the novel global FAAH inhibitors ARN14633 and ARN14280 elicit significant anti-hyperalgesic effects in a migraine-specific animal model and inhibit the associated peptidergic-inflammatory response. Although the precise mechanism underlying these effects remains to be elucidated, our results support further investigational studies of FAAH blockade as a potential therapeutic strategy to treat migraine conditions.

Fluorescence of ocular surface in a Covid -19 patient after Favipiravir treatment: a case report.

BACKGROUND: Favipiravir is used in treatment of Covid-19 patients. We aimed to share of ocular surface fluorescence in a patient after Favipiravir treatment in this case report. CASE PRESENTATION: A 20-year-old male patient declared no known systemic disease prior to Covid-19. He applied to us with blurry vision and blue light reflection after Covid-19 treatment with Favipiravir. We observed bilateral fluorescence on his eyes and fluorescence of his nails. Biomicroscopic examination was insignificant. CONCLUSION: We investigated the fluorescence of favipiravir tablets under ultraviolet light. Drug demonstrated fluorescence. We recorded the favipiravir fluorescence in-vitro. This appears to be a strong evidence in terms of the linkage between the fluorescence of the ocular surface and favipiravir.

Effectiveness of favipiravir in COVID-19: a live systematic review.

We performed a systematic review and meta-analysis for the effectiveness of Favipiravir on the fatality and the requirement of mechanical ventilation for the treatment of moderate to severe COVID-19 patients. We searched available literature and reported it by using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Until June 1, 2021, we searched PubMed, bioRxiv, medRxiv, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar by using the keywords "Favipiravir" and terms synonymous with COVID-19. Studies for Favipiravir treatment compared to standard of care among moderate and severe COVID-19 patients were included. Risk of bias assessment was performed using Revised Cochrane risk of bias tool for randomized trials (RoB 2) and ROBINS-I assessment tool for non-randomized studies. We defined the outcome measures as fatality and requirement for mechanical ventilation. A total of 2702 studies were identified and 12 clinical trials with 1636 patients were analyzed. Nine out of 12 studies were randomized controlled trials. Among the randomized studies, one study has low risk of bias, six studies have moderate risk of bias, and 2 studies have high risk of bias. Observational studies were identified as having moderate risk of bias and non-randomized study was found to have serious risk of bias. Our meta-analysis did not reveal any significant difference between the intervention and the comparator on fatality rate (OR 1.11, 95% CI 0.64-1.94) and mechanical ventilation requirement (OR 0.50, 95% CI 0.13-1.95). There is no significant difference in fatality rate and mechanical ventilation requirement between Favipiravir treatment and the standard of care in moderate and severe COVID-19 patients.

Favipiravir for the treatment of patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Favipiravir possesses high utility for treating patients with COVID-19. However, research examining the efficacy and safety of favipiravir for patients with COVID-19 is limited. METHODS: We conducted a systematic review of published studies reporting the efficacy of favipiravir against COVID-19. Two investigators independently searched PubMed, the Cochrane Database of Systematic Reviews, MedRxiv, and ClinicalTrials.gov (inception to September 2020) to identify eligible studies. A meta-analysis was performed to measure viral clearance and clinical improvement as the primary outcomes. RESULTS: Among 11 eligible studies, 5 included a comparator group. Comparing to the comparator group, the favipiravir group exhibited significantly better viral clearance on day 7 after the initiation of treatment (odds ratio [OR] = 2.49, 95% confidence interval [CI] = 1.19-5.22), whereas no difference was noted on day 14 (OR = 2.19, 95% CI = 0.69-6.95). Although clinical improvement was significantly better in the favipiravir group on both days 7 and 14, the improvement was better on day 14 (OR = 3.03, 95% CI = 1.17-7.80) than on day 7 (OR = 1.60, 95% CI = 1.03-2.49). The estimated proportions of patients with viral clearance in the favipiravir arm on days 7 and 14 were 65.42 and 88.9%, respectively, versus 43.42 and 78.79%, respectively, in the comparator group. The estimated proportions of patients with clinical improvement on days 7 and 14 in the favipiravir group were 54.33 and 84.63%, respectively, compared with 34.40 and 65.77%, respectively, in the comparator group. CONCLUSIONS: Favipiravir induces viral clearance by 7 days and contributes to clinical improvement within 14 days. The results indicated that favipiravir has strong possibility for treating COVID-19, especially in patients with mild-to-moderate illness. Additional well-designed studies, including examinations of the dose and duration of treatment, are crucial for reaching definitive conclusions.

Suspected cholestatic liver injury induced by favipiravir in a patient with COVID-19.

Favipiravir is an antiviral drug that is expected to have a therapeutic effect on SARS-CoV2 infection. Teratogenicity and hyperuricemia are known as the main side effects of favipiravir, but little is known about other side effects. This report describes a case of cholestatic liver injury induced by favipiravir. A 73-year-old Japanese with a history of alcoholic hepatitis was infected with SARS-CoV2. Drug therapy was instituted with lopinavir/ritonavir combined with interferon ß-1b. However, his condition worsened despite additional support with continuous hemodiafiltration and veno-venous extracorporeal membrane oxygenation. We suspected complications of bacterial pneumonia and started favipiravir in addition to antimicrobial therapy. Favipiravir was administered at 6000 mg/day on the first day and 2400 mg/day for the second and subsequent days for 14 days. After the initiation of antibiotics, transaminase and total bilirubin were elevated, suggesting a transient cholestasic liver dysfunction. The liver dysfunction in this case may have been triggered by antibacterial treatment, and high dose of favipiravir may have promoted the deterioration of liver function. Monitoring of liver function is vital and close attention should be paid when using favipiravir at high doses or in patients with impaired liver function.

Tolerability profile of topical cannabidiol and palmitoylethanolamide: a compilation of single-centre randomized evaluator-blinded clinical and in vitro studies in normal skin.

BACKGROUND: An increasing number of studies have investigated the adverse effect profile of oral cannabinoids; however, few studies have provided sufficient data on the tolerability of topical cannabinoids in human participants. AIM: To assess the tolerability profile of several commercial topical formulations containing cannabidiol (CBD) and palmitoylethanolamide (PEA) on the skin of healthy human participants. METHODS: Three human clinical trials and one in vitro study were conducted. The potential for skin irritation, sensitization and phototoxicity of several products, were assessed via patch testing on healthy human skin. The products assessed included two formulations containing CBD and PEA, one containing hemp seed oil and four concentrations of CBD alone. Ocular toxicity was tested using a traditional hen's egg chorioallantoic membrane model with three CBD, PEA and hemp seed oil formulations. RESULTS: There was no irritation or sensitization of the products evident via patch testing on healthy participants. Additionally, mild phototoxicity of a hemp seed oil product was found at the 48-h time point compared with the negative control. The in vitro experiment demonstrated comparable effects of cannabinoid products with historically nonirritating products. CONCLUSION: These specific formulations of CBD- and PEA-containing products are nonirritating and nonsensitizing in healthy adults, and further encourage similar research assessing their long-term safety and efficacy in human participants with dermatological diseases. There are some limitations to the study: (i) external validity may be limited as formulations from a single manufacturer were used for this study, while vast heterogeneity exists across unregulated, commercial CBD products on the market; and (ii) products were assessed only on normal, nondiseased human skin, and therefore extrapolation to those with dermatological diseases cannot be assumed.

The safety profile of favipiravir in COVID-19 patients with severe renal impairment.

OBJECTIVE: The safety profile of favipiravir in patients with severe renal impairment has not been investigated and available data are insufficient. The study aimed to compare the incidence of favipiravir-associated adverse events amongst patients with varying renal function statuses. METHODS: Records of 921 patients who were hospitalised for COVID-19 and had received at least 5 days of favipiravir treatment were retrospectively evaluated and 228 patients were included in the study. Patients' age, sex, comorbidities, estimated glomerular filtration rate (eGFR) and haematological and biochemical values were recorded. The incidence of adverse events was compared with the age, sex, comorbidities and eGFR of the patients. RESULTS: The mean age of the patients was 59.3 ± 15.6 years, and 38.2% of the patients were women. One hundred and thirty-one (57.5%) patients had experienced adverse events. These adverse effects consisted of ALT elevation (35.5%), AST elevation (21.5%), anaemia (16.2%), hyperuricaemia (10.5%), hepatocellular injury (9.2%), neutropenia (3.5%) and thrombocytopenia (2.6%). The incidence of adverse events was not significantly different when patients had eGFR >60 mL/min/1.73 m2 or eGFR 30-60 mL/min/1.73 m2 (P > .05), but significantly increased when the eGFR dropped to <30 (P < .05). The differences seen with hyperuricaemia and anaemia were significant (P < .05). CONCLUSION: Even though favipiravir appeared to be well tolerated in the individuals with renal failure in this study, its use in this population remains a challenge that requires more research and analysis.

Observational study of the effects of Favipiravir vs Lopinavir/Ritonavir on clinical outcomes in critically Ill patients with COVID-19.

WHAT IS KNOWN AND OBJECTIVES: In November 2019, several patients were diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China. So far, there are no specific treatments with proven high efficacy in patients with SARS-CoV-2. Presently, several drugs, such as hydroxychloroquine, ribavirin, favipiravir (FVP), lopinavir/ritonavir (LPV/r), remdesivir and oseltamivir, have been suggested as effective treatments for SARS-CoV-2. The aim of this study was to describe the clinical experience with FPV and LPV/r in critically ill patients with COVID-19 at Sakarya University Education and Research Hospital. METHODS: The study included 107 consecutive patients who had a laboratory confirmation of COVID-19 and were admitted to the intensive care unit (ICU) between 19 March and 19 May 2020. Follow-up continued through 30 May 2020 when the last observed patients were discharged. RESULTS AND DISCUSSION: Of the 107 patients, 65 received FPV (Group FPV) and 42 received LPV/r (Group LPV/r). The two groups were similar in terms of demographic data and clinical findings. 43 (66.2%) of the 65 patients in the FPV group and 23 (54.8%) of the 42 patients in the LPV/r group died (p = 0.237). The median ICU stay was 6.6 (IQR, 3-10) days in the FPV group and 9 (IQR, 6-16) days in the LPV/r group, which was a statistically significant difference (p = 0.010). WHAT IS NEW AND CONCLUSION: The length of hospital stay was significantly lower in the FVP group compared to the LPV/r group among patients who were discharged from the ICU. Although the analysis was done with a limited number of patients and the observed difference in mortality rate is of some concern, FVP treatment may be more beneficial than LPV/r in terms of effective use in the ICU.

A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19.

Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.).

Safety and tolerability of elbasvir/grazoprevir in chronic hepatitis C virus therapy: Integrated analysis from clinical trials.

Direct-acting antiviral treatments for chronic hepatitis C virus (HCV) infection are generally safe; however, understanding the safety profile of each regimen is essential for their continued use. Safety data were pooled from 12 clinical trials of elbasvir/grazoprevir (EBR/GZR) that enrolled adult participants with HCV infection. Pooled analyses are presented for participants receiving EBR/GZR for 12 weeks and those receiving EBR/GZR plus ribavirin (RBV) for 16-18 weeks. Safety data are also presented for participants with comorbidities receiving EBR/GZR for 12 weeks in individual clinical trials (chronic kidney disease [CKD] stage 4/5, inherited blood disorders [IBLD] or receiving opioid agonist therapy [OAT]). Among 1743 participants receiving EBR/GZR for 12 weeks, 1068 (61.3%) reported ≥1 adverse event (AE) and 491 had AEs (28.2%) considered drug-related. The most frequent AEs were headache (10.6%), fatigue (8.7%), nasopharyngitis (5.8%), nausea (5.1%) and diarrhoea (5.0%). Serious AEs were reported by 37 participants (2.1%), and 12 (0.7%) discontinued treatment due to an AE. In populations with CKD 4/5 or IBLD or receiving OAT, safety was similar in participants receiving EBR/GZR for 12 weeks and those receiving placebo. Some AEs occurred at higher frequencies in participants receiving RBV compared with those receiving EBR/GZR alone: fatigue (32.7% vs 8.7%); headache (21.6% vs 10.6%); and nausea (15.8% vs 5.1%). Safety was similar in participants with and those without cirrhosis. Grade 3/4 alanine aminotransferase elevations were reported in 0.7% participants. EBR/GZR is a safe treatment option for individuals with HCV genotype (GT) 1 or GT4 infections, even those with challenging comorbidities such as CKD or IBLD and those receiving OAT.

Real-world experience of elbasvir/grazoprevir in Taiwan: This study was focused on liver and renal adverse effects.

Elbasvir/grazoprevir with or without ribavirin has excellent efficacy and safety for the treatment of hepatitis C virus (HCV) genotype 1 and 4 patients. The real-world experience has been reported but the detailed analysis of liver and renal adverse effects is lacking. This study evaluated the real-world experience relating to the effectiveness and liver/renal safety of elbasvir/grazoprevir in HCV genotype 1 patients with compensated liver disease. In the four medical centres of Chang Gung Medical System, 350 HCV genotype 1 patients with compensated liver disease who were treated with elbasvir/grazoprevir were enrolled. Clinical characteristics and laboratory data were collected. The effectiveness (sustained virologic response 12 weeks after end of treatment, SVR12) and safety were assessed. A consecutive series of 350 patients with a mean age of 68.8 ± 10.0 years old were enrolled. The majority were treatment-naïve (72.3%), genotype 1b (97.7%) and advanced fibrosis/cirrhosis (94.3%). Seventy-nine (22.6%) had hepatocellular carcinoma and 23 (6.6%) had coinfection with hepatitis B. The effectiveness of SVR12 was 94.6% (95% CI: 92.2%-97.0%) in the full analysis set and 99.1% (95% CI: 98.1%-100.1%) in the per-protocol set. There were two relapses and one nonresponder. Seven (2.0%) patients had adverse events resulting in premature discontinuation of treatment. Five of them were considered drug-related. One was due to autoimmune hepatitis. Contrary to previous reports, around 49% of ALT elevation was observed after 8 weeks, and in two patients was due to hepatitis B flares. As to the renal function during the course of therapy, a minor deterioration of eGFR was observed in patients with baseline eGFR ≥60 mL/min/1.73 m2 , but not in those with baseline eGFR <60, <60-30 or <30 mL/min/1.73 m2 . In this real-world data, elbasvir/grazoprevir was effective with few liver/renal adverse effects. One patient developed autoimmune hepatitis.