Diverse effects of clarithromycin and proposal of its clinical application for treating COVID-19 as a repurposing drug.

Outbreak of SARS-CoV-2 has been declared a pandemic, which is a serious threat to human health. The disease was named coronavirus disease 2019 (COVID-19). Until now, several vaccines and a few drugs have been approved for the prevention and treatment for COVID-19. Recently, the effect of some macrolides including clarithromycin (CAM) on COVID-19 has attracted attention. CAM is known to have diverse effects including immunomodulatory and immunosuppressive effects, autophagy inhibition, steroid sparing effect, reversibility of drug resistance, antineoplastic effect, antiviral effect as well as bacteriostatic/bactericidal effect. Many patients with COVID-19 died due to an overwhelming response of their own immune system characterized by the uncontrolled release of circulating inflammatory cytokines (cytokine release syndrome [CRS]). This CRS plays a major role in progressing pneumonia to acute respiratory distress syndrome (ARDS) in COVID-19 patients. It is noteworthy that CAM can suppress inflammatory cytokines responsible for CRS and also has anti-SARS-CoV-2 effect. Considering the rapidly progressive global disease burden of COVID 19, the application of CAM for treating COVID-19 needs to be urgently evaluated. Recently, an open-labeled non-randomized trial using CAM for treating COVID-19 (ACHIEVE) was initiated in Greece in May, 2020. Its results, though preprint, indicated that CAM treatment of patients with moderate COVID-19 was associated with early clinical improvement and containment of viral load. Thus, treatment with CAM as a single agent or combined with other anti-SARS CoV-2 drugs should be tried for treating COVID-19. In this article, we discussed the significance and usefulness of CAM in treating COVID-19.

Diverse effects of clarithromycin and proposal of its clinical application for treating COVID-19 as a repurposing drug

@#Outbreak of SARS-CoV-2 has been declared a pandemic, which is a serious threat to human health. The disease was named coronavirus disease 2019 (COVID-19). Until now, several vaccines and a few drugs have been approved for the prevention and treatment for COVID-19. Recently, the effect of some macrolides including clarithromycin (CAM) on COVID-19 has attracted attention. CAM is known to have diverse effects including immunomodulatory and immunosuppressive effects, autophagy inhibition, steroid sparing effect, reversibility of drug resistance, antineoplastic effect, antiviral effect as well as bacteriostatic/bactericidal effect. Many patients with COVID-19 died due to an overwhelming response of their own immune system characterized by the uncontrolled release of circulating inflammatory cytokines (cytokine release syndrome [CRS]). This CRS plays a major role in progressing pneumonia to acute respiratory distress syndrome (ARDS) in COVID-19 patients. It is noteworthy that CAM can suppress inflammatory cytokines responsible for CRS and also has anti-SARS-CoV-2 effect. Considering the rapidly progressive global disease burden of COVID- 19, the application of CAM for treating COVID-19 needs to be urgently evaluated. Recently, an open-labeled non-randomized trial using CAM for treating COVID-19 (ACHIEVE) was initiated in Greece in May, 2020. Its results, though preprint, indicated that CAM treatment of patients with moderate COVID-19 was associated with early clinical improvement and containment of viral load. Thus, treatment with CAM as a single agent or combined with other anti-SARSCoV- 2 drugs should be tried for treating COVID-19. In this article, we discussed the significance and usefulness of CAM in treating COVID-19.

HLA-B is the best candidate of susceptibility genes in HLA for Japanese ulcerative colitis.

Recently, a genome-wide association study for ulcerative colitis (UC) in the UK population was reported, and several susceptibility loci including the human leukocyte antigen (HLA) region were identified. The strongest association in the HLA region was found at a 400 kb haplotype block containing HLA-DRB1. In Japanese population, previous study suggested the association between UC and HLA-B*52; however, HLA typing was determined using serotyping with the small sample size. The purpose of this study was to perform an association study in HLA-B by genotyping. A total of 320 patients with UC and 322 healthy controls were recruited in this case-control study. All subjects were Japanese. Genotyping of HLA-B was performed by polymerase chain reaction using a sequence-specific primer. When the allele frequencies were compared, significant associations were found with B*52 [odds ratio (OR) = 3.65, P = 1.6 x 10(-17), P(c) = 3.7 x 10(-16)] and B*4002 (OR = 0.52, P = 0.00030, P(c) = 0.0068). The allele frequency of B*52 was significantly higher in patients diagnosed before 40 years of age than in those diagnosed after 40 years (OR = 1.79, P = 0.010, P(c) = 0.020). A combination association map of Japanese UC using our current and previous studies showed two equal peaks of association on HLA-DRB1 and HLA-B, indicating the possible existence of two casual variants in the HLA region inside and outside the 400 kb block found in UK. We conclude that HLA-B contributes to the susceptibility to Japanese UC, especially cases with younger age of onset. The strength of association for HLA-B was equal to that for HLA-DRB1 in Japanese UC, in contrast to the UK population.

Mechanism of sodium load-induced hypertension in non-insulin dependent diabetes mellitus model rats: defective dopaminergic system to inhibit Na-K-ATPase activity in renal epithelial cells.

Obesity-related non-insulin dependent diabetes mellitus (NIDDM) is frequently accompanied by hypertension. The present study was designed to clarify this mechanism. We first determined the blood pressure in male Wistar fatty rats (WFR), one of the NIDDM model rats, and in Wistar lean rats (WLR) as the control, with a normal (0.7% NaCl) or high (7% NaCl) salt diet. We observed no difference in systolic and mean blood pressures between WFR and WLR. WFR, however, became extremely hypertensive as a result of ingesting the high salt diet. We next investigated the mechanism for sodium sensitivity in WFR. Although the urinary excretion of dopamine (DA), a potent natriuretic factor, which reflects the ability for renal DA production, was preserved in WFR, the sodium balance with the high salt diet was positive. Moreover, Na-K-ATPase activity in isolated proximal convoluted tubules (PCT) from WFR with a normal salt diet was significantly (p<0.05) higher than that from WLR. A high salt load produced a significant (p<0.05) decrease in Na-K-ATPase activity in WLR but not in WFR. Similarly, Na-K-ATPase activity in WLR with a normal salt diet was significantly (p<0.05) inhibited by DA (10(-5) M), but this was not true in WFR. Furthermore, urinary excretion of norepinephrine in WFR with a high salt diet was the highest among all the groups. These results indicate that WFR tend to develop salt-sensitive hypertension that could be caused by the excessive sodium retention occurring as the results of a defective dopaminergic system in the kidney that fails to inhibit Na-K-ATPase activity. Augmentation of the renal sympathetic nervous system may play some role in this setting.

Radiographic observations on root resorption in the primary dentition.

In order to construct standardized charts for root resorption in the primary dentition of Japanese children, we investigated the stages of resorption (1/4, 1/2 and 3/4 of the root) based on the criterion of Fanning, et al. using 11,167 panoramic radiographs (5,759 of boys and 5,408 of girls). The following information was obtained. 1) The root resorption for a tooth on one side was the same as for its counterpart on the other side regardless of differences in sex or arch. 2) The average age for each root resorption stage was lower in girls than in boys regardless of differences in sex or arch. 3) The average age for each root resorption stage was lower in the mandible than in the maxilla for every tooth. 4) In the maxilla, the period between 1/4 to 3/4 resorption of the root was greater in the primary molars than in the primary anterior teeth. However, the opposite was true in the mandible. 5) Although no difference was observed between the maxilla and the mandible in the resorption period for the primary incisors and canines, the resorption time for the primary molars was greater in the maxilla than in the mandible. 6) When the relationship was observed between the resorption stages for each tooth and the calcification stages for the corresponding successional permanent tooth. a) With the exception of the maxillary and mandibular canines, the average age for 1/4 resorption of the primary root corresponded to the period between completion of the permanent crown and initial root formation of the successional permanent tooth. b) With the exception of the maxillary and mandibular canines, and the mandibular second premolars, the average age for 3/4 resorption of the primary root corresponded to the period between 1/4 and 1/2 formation of the root of the successional permanent tooth. From these results, standardized charts were constructed for the resorption of the roots of primary teeth in Japanese children. These standardized charts are useful in daily clinical practice in such areas as endodontic treatment of primary teeth and orthodontics.

Calcification of the permanent first molars observed in panoramic radiographs.

We investigated the development (calcification) stages of the permanent first molars of Japanese children by classifying them into 14 stages by the criterion of Moorrees, et al., using 11,167 panoramic radiographs, 5,759 of boys and 5,408 of girls, between the ages of 2 years 0 months and 14 years 11 months. The following information was obtained from calculations of the average chronological ages for the development stages of these teeth. 1) The development of first molars was earlier in girls than boys. This was particularly true during the middle phase of development. 2) A first molar on one side developed at the same rate as its counterpart on the other side, regardless of differences in sex or arch. 3) In both boys and girls, the development of the mandibular first molars was about one month earlier than that of the maxillary first molars at each stage. 4) When these results were compared with those of Nolla, Moorrees and Haavikko, who pioneered this field of study, it was clear that the development of the teeth in Japanese is different from that in Caucasians. 5) We made charts of the development of the first molars in Japanese which can be applied in routine clinical practice.