Intravenous tocilizumab versus standard of care in the treatment of severe and critical COVID-19-related pneumonia: A single center, double-blind, placebo controlled, phase 3 trial

Background@#Severe and critical COVID-19 disease is characterized by hyperinflammation involving pro-inflammatory cytokines, particularly IL-6. Tocilizumab is a monoclonal antibody that blocks IL-6 receptors. @*Objectives@#This study evaluated the efficacy of tocilizumab in Filipino patients with severe to critical COVID-19 disease. @*Methods@#This phase 3 randomized double-blind trial, included patients hospitalized for severe or critical COVID-19 in a 1:1 ratio to receive either tocilizumab plus local standard of care or placebo plus standard of care. Patients were eligible for a repeat IV infusion within 24-48 hours if they deteriorated or did not improve. Treatment success or clinical improvement was defined as at least two categories of improvement from baseline in the WHO 7-point Ordinal Scale of patient status, in an intention-to-treat manner. @*Results@#Forty-nine (49) patients were randomized in the tocilizumab arm and 49 in the placebo arm. There was no significant difference in age, comorbidities, COVID-19 severity, need for mechanical ventilation, presence of acute respiratory distress syndrome, or biomarker levels between groups. Use of adjunctive therapy was similar between groups, with corticosteroid used in 91.8% in tocilizumab group and 81.6% in the placebo group, while remdesivir was used in 98% of participants in both groups. There was no significant difference between groups in terms of treatment success in both the intention-to-treat analysis (relative risk=1.05, 95% CI: 0.85-1.30) and per-protocol analysis (relative risk=0.98, 95% CI: 0.80 to 1.21). There was no significant difference in time to improvement of at least two categories relative to baseline on the 7-point Ordinal Scale of clinical status. @*Conclusion@#The use of tocilizumab on top of standard of care in the management of patients with severe to critical COVID-19 did not result in significant improvement as defined by the WHO 7-point Ordinal Scale of patient status, nor in significant improvement in incidence of mechanical ventilation, incidence of ICU admission, length of ICU stay, and mortality rate.

Genetic polymorphisms in NAT1, NAT2, GSTM1, GSTP1 and GSTT1 and susceptibility to colorectal cancer among Filipinos

@#Objectives. Polymorphisms in metabolic genes which alter rates of bioactivation and detoxification have been shown to modulate susceptibility to colorectal cancer. This study sought to evaluate the colorectal cancer risk from environmental factors and to do polymorphism studies on genes that code for Phase I and II xenobiotic metabolic enzymes among Filipino colorectal cancer patients and matched controls. Methods. A total of 224 colorectal cancer cases and 276 controls from the Filipino population were genotyped for selected polymorphisms in GSTM1, GSTP1, GSTT1, NAT1 and NAT2. Medical and diet histories, occupational exposure and demographic data were also collected for all subject participants.Results. Univariate logistic regression of non-genetic factors identified exposure to UV (sunlight) (OR 1.99, 95% CI: 1.16-3.39) and wood dust (OR 2.66, 95% CI: 1.21-5.83) and moldy food exposure (OR 1.61, 95% CI:1.11-2.35) as risk factors; while the NAT2*6B allele (recessive model OR 1.51, 95% CI :1.06-2.16; dominant model OR 1.87, 95% CI: 1.05-3.33) and homozygous genotype (OR 2.19, 95% CI: 1.19-4.03) were found to be significant among the genetic factors. After multivariate logistic regression of both environmental and genetic factors, only UV radiation exposure (OR 2.08, 95% CI: 1.21-3.58) and wood dust exposure (OR 2.08, 95% CI: 0.95-5.30) remained to be significantly associated with increasing colorectal cancer risk in the study population.Conclusion. This study demonstrated that UV sunlight and wood dust exposure play a greater role in influencing colorectal cancer susceptibility than genotype status from genetic polymorphisms of the GST and the NAT` genes.

The prevalence of CYP2D6 Gene Polymorphisms among Filipinos and their use as biomarkers for lung cancer risk

Objectives@#The highly polymorphic nature of the CYP2D6 gene and its central role in the metabolism of commonly used drugs make it an ideal candidate for pharmacogenetic screening. This study aims to determine the prevalence of CYP2D6 polymorphisms among Filipinos and their association to lung cancer. @*Method@#Forty seven single nucleotide polymorphisms (SNPs) of the CYP2D6 gene were genotyped from DNA samples of 115 cases with lung cancer and age- and sex-matched 115 controls. @*Results@#Results show that 18 out of 47 polymorphisms have significant genotypic variability (>1% for at least 2 genotypes). No variant is associated with lung cancer. However, rs1135840, rs16947 and rs28360521, were found to be highly variable among Filipinos. @*Conclusion@#This study demonstrated that CYP2D6 polymorphisms are present among Filipinos, which, although not found to be associated with lung cancer, can be useful biomarkers for future pharmacogenetic studies. The SNP rs16947 is found to be associated with cancer and timolol-induced bradycardia; the SNP rs1135840, on the other hand, is only shown to be linked with cancer. The genetic variant rs28360521 is known to be associated with low-dose aspirin-induced lower gastrointestinal bleeding.