Review on Antifungal Agents

There are so many type of daisies are founded because of ‘Fungal’ such daisies given in follow. also the treatment on this particular daisies with the help of ‘Anti-fungal’ drug or anti- fungal agent and anti-fungal medication as follows The four main classes of antifungal drugs are the polyenes, Azoles, allylamines and echinocandins. Clinically useful “older” agents include topical azole Formulations (for superficial yeast and dermatophyte Infections), first-generation triazoles (fluconazole and Itraconazole, for a range of superficial and invasive fungal Infections), amphotericin B formulations (for a broad range of Invasive fungal infections) and terbinafine (for dermatophyte Infections). Clinically important “newer” agents include members of the Echinocandin class (eg, caspofungin) and second-generation Triazoles (eg, voriconazole and posaconazole). Voriconazole and posaconazole have broad-spectrum activity Against yeasts and moulds, including Aspergillus species. Posaconazole is the only azole drug with activity against Zygomycete fungi. Caspofungin and the other echinocandins are effective in Treating Candida and Aspergillus infections. The azoles are relatively safe, but clinicians should be aware of drug–drug interactions and adverse effects, including Visual disturbances (with voriconazole), elevations in liver Transaminase levels, and skin rashes. Caspofungin has Minimal adverse effects. Combination antifungal therapy may be appropriate in Selected patients with invasive fungal infections, but is Empiric and driven by individual physician practice. Clinical needs for novel antifungal agents have altered

Fenebrutinib in H1 antihistamine-refractory chronic spontaneous urticaria: a randomized phase 2 trial

Bruton’s tyrosine kinase (BTK) is crucial for FcεRI-mediated mast cell activation and essential for autoantibody production by B cells in chronic spontaneous urticaria (CSU). Fenebrutinib, an orally administered, potent, highly selective, reversible BTK inhibitor, may be effective in CSU. This double-blind, placebo-controlled, phase 2 trial (EudraCT ID 2016-004624-35) randomized 93 adults with antihistamine-refractory CSU to 50 mg daily, 150 mg daily and 200 mg twice daily of fenebrutinib or placebo for 8 weeks. The primary end point was change from baseline in urticaria activity score over 7 d (UAS7) at week 8. Secondary end points were the change from baseline in UAS7 at week 4 and the proportion of patients well-controlled (UAS7 ≤ 6) at week 8. Fenebrutinib efficacy in patients with type IIb autoimmunity and effects on IgG-anti-FcεRI were exploratory end points. Safety was also evaluated. The primary end point was met, with dose-dependent improvements in UAS7 at week 8 occurring at 200 mg twice daily and 150 mg daily, but not at 50 mg daily of fenebrutinib versus placebo. Asymptomatic, reversible grade 2 and 3 liver transaminase elevations occurred in the fenebrutinib 150 mg daily and 200 mg twice daily groups (2 patients each). Fenebrutinib diminished disease activity in patients with antihistamine-refractory CSU, including more patients with refractory type IIb autoimmunity. These results support the potential use of BTK inhibition in antihistamine-refractory CSU.

Effectiveness, tolerability and safety of Direct Acting Antivirals in Mexican individuals with Hepatitis C virus genotype-1 and previous pegylated interferon and ribavirin therapy

Background Direct Acting Antivirals (DAAs) represent a large improvement in the treatment of chronic hepatitis C, resulting in <90% sustained virological response (SVR). There are no reports on the real-world DAA response for Mexico and few reports exist for Latin America. The aim of the study was to report SVR, and immediate benefits with the DAA treatments sofosbuvir, ledispavir, with/without ribavirin (SOF/LDV ± RBV) and ombitasvir, paritaprevir, ritonavir, dasabuvir with/without RBV (OBV/PTV/r/DSV ± RBV) in patients with viral genotype 1a or 1b, and who did not respond to previous peginterferon/ribavirin (PegIFNα2a+RBV) therapy. Methods A descriptive, ambispective, longitudinal study was conducted. A cohort of 261 adult patients received PegIFNα2a+RBV therapy before 2014; 167 (64%) did not respond, 83 of these were subsequently treated with SOF/LDV ± RBV or OBV/PTV/r/DSV ± RBV. Child-Pugh-Score (CPS), Fibrosis-4 (FIB-4), and AST to Platelet Ratio Index (APRI) were evaluated before and after treatment. Results SVR with PegIFNα2a+RBV was 36%, and 97.5% with DAAs. CPS, FIB-4 and APRI improved significantly after DAA treatment, mainly because of liver transaminase reduction. Conclusions DAA treatment showed excellent SVR rates in Mexican patients who had not responded to PegIFNα2a+RBV therapy. Improvement in CPS, FIB-4 and APRI without improvement in fibrosis was observed in cirrhotic and non-cirrhotic patients, as well as considerable reduction in liver transaminases, which suggests a reduction in hepatic necroinflammation.

TUBB3 E410K Syndrome With Childhood-Onset Nonalcoholic Steatohepatitis

Context Nonalcoholic fatty liver disease (NAFLD) is becoming a major issue worldwide, even in children. Multiple parallel hits hypothesis has been suggested as progress of NAFLD, but the mechanism of NAFLD is not completely understood. β-Tubulin is essential in mitoses, neuronal migration, and axon guidance during neuronal development. Pathogenic variants in the TUBB3 gene were shown to be associated with a wide spectrum of neurological abnormalities, but not accompanied by hepatic complications, such as NAFLD. Objective This work aims to examine the association between TUBB3 mutation and nonalcoholic steatohepatitis (NASH). Methods An 11-year-old girl has been followed up as having atypical Möbius syndrome since infancy, as she was born with bilateral ptosis, paralytic strabismus, and facial weakness. At age 7 years, she was diagnosed with TUBB3 E410K syndrome by whole-exome sequencing. At age 10 years, her blood examination revealed elevated liver transaminase levels, which persisted for almost 2 years. She underwent liver biopsy, the results of which were suggestive of NASH. Results The expression of TUBB3 was absent, but that of tyrosine hydroxylase (TH) was present in the parenchymal nerve fibers of the liver. On the other hand, in comparison with an autopsy case of NASH and a normal control, these showed coexpression of TUBB3 and TH in the liver. Conclusion We report the first case of TUBB3 E410K syndrome accompanied by NASH. This case suggests that the TUBB3 mutation may be associated with the pathogenesis and progression of NASH in humans.

Case Report: Isolated Cystic Dilatation of the Cystic Duct: A Misdiagnosed Case Preoperatively

A 33-year-old female with a mild elevation of liver transaminase was sent to the general surgery department for medical services due to upper-right abdominal pain for 2 weeks. A liquid dark area ~4 × 3 × 3 cm in size in the theoretical location of the pancreatic segment of the common bile duct was detected by abdominal CT with no enhancement of the cystic wall found in the enhanced CT scan. The patient was then diagnosed with a choledochal cyst based on the results of the radiological images preoperatively. During the operation, the isolated cystic dilatation was found in the middle part of the cystic duct, and its caudal portion was found behind the head of the pancreas and converged into the common bile duct at an acute angle and low insertion. According to the intraoperative evaluation, the female was then diagnosed with a cystic duct cyst (CDC). The surgery was converted to a laparotomy for the unclear structure and the possibility of anatomic variation of the bile duct. The caudal portion of the cystic duct was found communicated with the common bile duct with a narrow base, and the extrahepatic bile duct was not cystic. The CDC was removed in the surgery. One week later, the patient was discharged from the hospital for the disappearance of abdominal pain and normal liver transaminase and did not report any discomfort in the 1-month-long follow-up. The lessons drawn from this case were as follows: (1) the distinction between the relatively frequent choledochal cyst and the isolated CDC should always be taken in mind; (2) a surgical strategy should be given priority for an intraoperatively confirmed CDC; (3) a common bile duct exploration is recommended for patients with choledocholithiasis or jaundice.

Elevations in Liver Transaminases in COVID-19: (How) Are They Related?

Liver involvement in COVID-19 is not yet well-understood, but elevations in liver transaminases have been described to occur in 14–53% of the cases and are more frequently seen in severe disease. This cross-sectional study explored the relationship between the elevations in liver transaminases and inflammatory parameters in 209 adults with COVID-19. Demographic and clinical data, serum levels of inflammatory cytokines and liver aminotransferases were analyzed. Three groups were formed according to the liver transaminase abnormalities: (I) Normal transaminases, (II) Borderline transaminases elevation, and (III) Mild to severe transaminases elevation. Altered liver transaminases were directly related to disease severity, showing association with the NEWS2 score at admission and greater need for ICU or death. Moreover, higher levels of IL-2 and CRP were associated with borderline transaminases elevations, whereas higher levels of IL-10 and Neutrophil to Lymphocyte ratio were associated with mild to severe transaminases elevation. These results reinforce the importance of liver transaminases in patients with COVID-19 as a complementary marker for disease severity and also point to them as a parameter reflecting the continuous dynamics between viral infection and the immune response.

Glycogenic Hepatopathy in a Patient with Pancreatogenic Diabetes

Glycogenic hepatopathy is characterized by acute liver injury secondary to reversible accumulation of excess glycogen in hepatocytes. This phenomenon has been described in type 1 diabetes, with few cases reported in patients with type 2 diabetes. Glycogenic hepatopathy in the setting of pancreatogenic (type 3c) diabetes has yet to be reported. A 57-year-old female with a history of insulin-requiring pancreatogenic diabetes mellitus secondary to alcohol-induced chronic pancreatitis status post distal pancreatectomy presented with recurrent admissions for abdominal pain, hyperglycemia, hyperosmolar hyperglycemic state (HHS), and unexplained elevation of liver transaminase levels. Glycemic control remained poor over many years with consistently elevated HbA1c in the setting of labile blood sugars, medication noncompliance, and lifestyle non-adherence. The patient was admitted to the hospital with altered mental status and markedly elevated blood glucose (1,182 mg/dL) concerning for HHS. On admission, her liver function tests (LFTs) revealed elevated alkaline phosphatase (1,011 U/L, n &lt;150 U/L), AST (583 U/L, n &lt;34 U/L), and ALT (517 U/L, n &lt;55 U/L). Direct and total bilirubin were within normal limits. The patient underwent extensive workup including drug and toxin levels, autoimmune evaluation, serology for infectious causes, abdominal computed tomography scanning, right upper quadrant ultrasound, and magnetic resonance cholangiopancreatography (MRCP). All laboratory workup was negative, ultrasound was unremarkable, and MRCP showed no evidence of biliary or common bile duct dilatation. Throughout her hospitalization, LFTs gradually improved with optimization of blood glucose. Less than one week later, the patient returned with blood glucose of 673 mg/dL and LFTs notable for alkaline phosphatase 789 U/L, AST 1,068 U/L, and ALT 299 U/L. Again, all testing was negative for causes of rapid increase in liver enzymes. Similar to previous admissions, her LFTs improved with resolution of hyperglycemia. Review of electronic medical record revealed a similar trend during previous admissions. The patient did not undergo liver biopsy; however, the parallel relationship of LFTs and hyperglycemia, in the absence of radiologic or laboratory evidence of alternate liver pathology, supports the diagnosis of glycogenic hepatopathy. This is the first case of glycogenic hepatopathy reported in a patient with pancreatogenic diabetes. Due to the rarity of this condition and minimal literature of its occurrence in adult non-type-1 diabetics, glycogenic hepatopathy is likely infrequently considered when evaluating patients with recurrent hyperglycemia and elevated LFTs. This case accentuates the need for further research of this condition in non-type 1 diabetics as the prognosis and management differ from other forms of acute liver injury.

One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency

Purpose To assess olipudase alfa enzyme replacement therapy for non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children. Methods This phase 1/2, international, multicenter, open-label trial (ASCEND-Peds/NCT02292654) administered intravenous olipudase alfa every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary outcome was safety through week 64. Secondary outcomes included pharmacokinetics, spleen and liver volumes, lung diffusing capacity (DLCO), lipid profiles, and height through week 52. Results Twenty patients were enrolled: four adolescents (12–17 years), nine children (6–11 years), and seven infants/early child (1–5 years). Most adverse events were mild or moderate, including infusion-associated reactions (primarily urticaria, pyrexia, and/or vomiting) in 11 patients. Three patients had serious treatment-related events: one with transient asymptomatic alanine aminotransferase increases, another with urticaria and rash (antidrug antibody positive [ADA+]), and a third with an anaphylactic reaction (ADA+) who underwent desensitization and reached the 3 mg/kg maintenance dose. Mean splenomegaly and hepatomegaly improved by >40% (p < 0.0001). Mean % predicted DLCO improved by 32.9% (p = 0.0053) in patients able to perform the test. Lipid profiles and elevated liver transaminase levels normalized. Mean height Z-scores improved by 0.56 (p < 0.0001). Conclusion In this study in children with chronic ASMD, olipudase alfa was generally well-tolerated with significant, comprehensive improvements in disease pathology across a range of clinically relevant endpoints.

Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial

Type III interferons have been touted as promising therapeutics in outpatients with coronavirus disease 2019 (COVID-19). We conducted a randomized, single-blind, placebo-controlled trial (NCT04331899) in 120 outpatients with mild to moderate COVID-19 to determine whether a single, 180 mcg subcutaneous dose of Peginterferon Lambda-1a (Lambda) within 72 hours of diagnosis could shorten the duration of viral shedding (primary endpoint) or symptoms (secondary endpoint). In both the 60 patients receiving Lambda and 60 receiving placebo, the median time to cessation of viral shedding was 7 days (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.56 to 1.19). Symptoms resolved in 8 and 9 days in Lambda and placebo, respectively, and symptom duration did not differ significantly between groups (HR 0.94; 95% CI 0.64 to 1.39). Both Lambda and placebo were well-tolerated, though liver transaminase elevations were more common in the Lambda vs. placebo arm (15/60 vs 5/60; p = 0.027). In this study, a single dose of subcutaneous Peginterferon Lambda-1a neither shortened the duration of SARS-CoV-2 viral shedding nor improved symptoms in outpatients with uncomplicated COVID-19.