Esterases catalyze the hydrolysis of therapeutic drugs containing esters or amides in their structures. Human carboxylesterase (CES) and arylacetamide deacetylase (AADAC) are the major enzymes that ...catalyze the hydrolysis of drugs in the liver. Characterization of the enzyme(s) responsible for drug metabolism is required in drug development and to realize optimal drug therapy. Because multiple enzymes may show a metabolic potency for a given compound, inhibition studies using chemical inhibitors are useful tools to determine the contribution of each enzyme in human tissue preparations. The purpose of this study was to find specific inhibitors for human CES1, CES2, and AADAC. We screened 542 chemicals for the inhibition potency toward hydrolase activities of p-nitrophenyl acetate by recombinant CES1, CES2, and AADAC. We found that digitonin and telmisartan specifically inhibited CES1 and CES2 enzyme activity, respectively. Vinblastine potently inhibited both AADAC and CES2, but no specific inhibitor of AADAC was found. The inhibitory potency and specificity of these compounds were also evaluated by monitoring the effects on hydrolase activity of probe compounds of each enzyme (CES1: lidocaine, CES2: CPT-11, AADAC: phenacetin) in human liver microsomes. Telmisartan and vinblastine strongly inhibited the hydrolysis of CPT-11 and/or phenacetin, but digitonin did not strongly inhibit the hydrolysis of lidocaine, indicating that the inhibitory potency of digitonin was different between recombinant CES1 and liver microsomes. Although we could not find a specific inhibitor of AADAC, the combined use of telmisartan and vinblastine could predict the responsibility of human AADAC to drug hydrolysis.
Environmental fate of 58 pharmaceutical compounds (PhCs) grouped into 11 therapeutic classes in the three different waters, hospital effluent, sewage treatment plant (STP) and river water, was ...estimated by combination of their quantitative concentration analysis and evaluation of their extent of contribution as loading sources. At the same time, distribution of six classes of antimicrobial-resistant bacteria (AMRB) in the same water samples was estimated by screening of individual PhC-resistant microbes grown on each specific chromogenic medium. The results indicate that 48 PhCs were detected ranged from 1 ng/L (losartan carboxylic acid) to 228 μg/L (acetaminophen sulfate) in hospital effluent, and contribution of the pollution load derived from hospital effluent to STP influent was estimated as 0.1% to 15%. On the other hand, contribution of STP effluent to river water was high, 32% to 60% for antibacterials, antipertensives and X-ray contrast media. In the cases for AMRB, detected numbers of colonies of AMRB in hospital effluent ranged from 29 CFU/mL to 1805 CFU/mL, and the estimated contribution of the AMRB pollution load derived from hospital effluent to STP influent was as low as 0.1% (levofloxacin and olmesartan) to 5.1% (N-desmethyl tamoxifen). Although the contribution of STPs as loading sources of PhCs and AMRB in surface waters was large, ozonation as an advanced water treatment system effectively removed a wide range of both PhCs and AMRB in water samples. These results suggest the importance of reducing environmental pollutant loads (not only at STPs but also at medical facilities) before being discharged into the surface waters, to both conserve water and keep the water environment safe. To our knowledge, this is the first report to show the distribution and contribution of AMRB from hospital effluent to the surface waters.
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•A year-round monitoring survey of urban hospital effluent in Japan was performed.•58 pharmaceuticals and 6 drug-resistant bacteria in hospital effluent were surveyed.•Drug-resistant bacteria were detected at 29 to 1805 CFU/mL.•The hospital pharmaceutical pollution load of STP influent varied from 0.1% to 15%.•Ozone treatment effectively removed the targeted pollutants.
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•O3-MB was applied to remove 39 pharmaceuticals in 10 therapeutic classes in water.•Over 90% removal rate was obtained for 33 compounds (>80% for 37 compounds).•O3-MB enhanced removal ...efficiency by 8–34% relative to the conventional O3.•UV and/or H2O2 increased the reaction rate constant by 2.9–5.5 times relative to O3-MB.•MB treatment improved O3 consumption up to 2.8 times higher than O3 treatments.
Ozonated-microbubble (O3-MB) was applied to remove 39 pharmaceuticals in 10 therapeutic classes (ant-ivirals, anti-bacterials, anti-cancer drugs, psychotropics, anti-hypertensives, analgesic-antipyretics, contrast media, bronchodilators, anti-pruritics, and herbal medicines) in water and the results were compared with those given by O3 alone and combined treatments with UV, and/or H2O2, or both. The summarized results clearly indicate that O3-MB based treatments significantly (P < 0.01) enhanced removal rates by 8–34% to O3 alone, and removal rates of >90% (>80%) were attained for 33 (37) compounds. Introduction of MB technology was indispensable to improve degradation of famciclovir (anti-viral), bicalutamide (anti-cancer), sulpiride (phychotropic) and acetaminophen glucuronide (analgesic-antipyretic) over 96.0%. Recalcitrant properties of all contrast media type compounds (iohexol, ioversol, iopromide, iomeprol and iopamidol) against both O3 and O3-MB were significantly improved by combined treatment with UV, and removal rates became 93.8–98.8% from 0% to 52.0%, indicating effectiveness of combined use of photolysis more than oxidation by hydroxyl radicals. Combination of UV and/or H2O2 with O3-MB increased the reaction rate constant by 2.9–5.5 times in average relative to O3 and O3-MB. In addition, MB treatment improved O3 consumption up to 2.8 times higher than the O3 treatments. These results indicate that the combined treatments of O3-MB with UV and/or H2O2 could minimize the environmental pollutant load of pharmaceuticals discharged into rivers. To the best of our knowledge, this is the first investigation which showed enhancement of removal rates of multiple pharmaceuticals together with combined use of UV and/or H2O2.
In primary Sjögren's syndrome, it is extremely rare to observe subacute progressive lower-body parkinsonism with severe sensory hearing loss responsive to corticosteroid therapy. Sjögren's syndrome ...can cause heterogeneous symptoms; therefore, its diagnosis and introduction of treatment are prone to be delayed, particularly in cases without sicca symptoms or seronegative cases, which are more likely to be seen in patients with neurological complications. This report may help clinicians identify atypical early neurological symptoms in primary Sjögren's syndrome.
A heterozygous loss-of-function variant in lin-28 homolog A (LIN28A) was recently reported as a novel pathogenic gene in patients with PD from Korea. Two patients harboring LIN28A variants had early- ...or middle-aged-onset PD with good responses to levodopa. In the current study, we aimed to identify the prevalence of LIN28A variants among PD patients of Japanese origin. We performed genetic sequencing of 284 patients with early-onset PD. We then estimated the frequency and functional effect of each variant using prediction tools. We identified three different rare variants in LIN28A (rs4623750, c.228 + 49 C > T; rs199541048, c.*7 A > G; and rs4659441, c.*43 C > T). The frequency of each variant in the PD patients did not differ from that of the general population. No variants were identified in the amino acid-coding regions. Our results do not support a strong association of LIN28A with early-onset PD among Japanese patients.
We evaluated the environmental fate of new three anti-influenza drugs, favipiravir (FAV), peramivir (PER), and laninamivir (LAN), and an active prodrug of LAN, laninamivir octanoate (LANO), in ...comparison with four conventional drugs, oseltamivir (OS), oseltamivir carboxylate (OC), amantadine (AMN), and zanamivir (ZAN) by photodegradation, biodegradation, and sorption to river sediments. In addition, we conducted 9-month survey of urban rivers in the Yodo River basin from 2015 to 2016 (including the influenza season) to investigate the current status of occurrence of these drugs in the river environment.
The results clearly showed that FAV and LAN rapidly disappeared through photodegradation (half-lives 1 and 8 h, respectively), followed by LANO which gradually disappeared through biodegradation (half-life, 2 days). The remained PER and conventional drugs were, however, persistent and transported from upstream to downstream sites. Rates of their sorption to river sediments were negligibly small. Detected levels remained were in the range from N.D. to 89 ng/L for the river waters and from N.D. to 906 ng/L in sewage effluent. However, all of the remained drugs were effectively removed by ozonation after chlorination at a sewage treatment plant.
These findings suggest the importance of introducing ozonation for reduction of pollution loads in rivers, helping to keep river environments safe. To the best of our knowledge, this is the first evaluation of the removal effects of natural sunlight, biodegradation, and sorption to river sediments on FAV, PER, LAN, LANO, and a conventional drug, AMN.
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•Environmental fate of new three anti-influenza drugs and one prodrug was evaluated.•Photolysis, biodegradation, and sorption experiments were conducted.•Nine-month monitoring survey of urban rivers in Japan was investigated.•Favipiravir and Laninamivir were rapidly removed through photodegradation.•Ozone treatment of sewage was effective for removal of anti-influenza drugs.
In primary Sjogren's syndrome, it is extremely rare to observe subacute progressive lower-body parkinsonism with severe sensory hearing loss responsive to corticosteroid therapy. Sjogren's syndrome ...can cause heterogeneous symptoms; therefore, its diagnosis and introduction of treatment are prone to be delayed, particularly in cases without sicca symptoms or seronegative cases, which are more likely to be seen in patients with neurological complications. This report may help clinicians identify atypical early neurological symptoms in primary Sjogren's syndrome.
Flutamide, an antiandrogen drug, is widely used for the treatment of prostate cancer. The major metabolic pathways of flutamide are hydroxylation and hydrolysis. The hydrolyzed metabolite, ...5-amino-2-nitrobenzotrifluoride (FLU-1), is further metabolized to N-hydroxy FLU-1, an assumed hepatotoxicant. Our previous study demonstrated that arylacetamide deacetylase (AADAC), one of the major serine esterases expressed in the human liver and gastrointestinal tract, catalyzes the flutamide hydrolysis. However, the enzyme kinetics in human tissue microsomes were not consistent with the kinetics by recombinant human AADAC. Thus, it seemed that AADAC is not the sole enzyme responsible for flutamide hydrolysis in human. In the present study, we found that recombinant carboxylesterase (CES) 2 could hydrolyze flutamide at low concentrations of flutamide. In the inhibition assay, the flutamide hydrolase activities at a flutamide concentration of 5 μM in human liver and jejunum microsomes were strongly inhibited by a selective CES2 inhibitor, 10 μM loperamide, with the residual activities of 22.9 ± 3.5 and 18.6 ± 0.7%, respectively. These results suggest that CES2 is also involved in the flutamide hydrolysis in human tissues. Using six individual human livers, the contributions of AADAC and CES2 to flutamide hydrolysis were estimated by using the relative activity factor. The relative contribution of CES2 was approximately 75 to 99% at the concentration of 5 μM flutamide. In contrast, the relative contribution of AADAC increased in parallel with the concentration of flutamide. Thus, CES2, rather than AADAC, largely contributed to the flutamide hydrolysis in clinical therapeutics.
Abstract
Background
Pisa syndrome (PS), characterized by lateral trunk flexion, is quite common in patients with Parkinson’s disease (PD). Patients with PS are older and have a significantly longer ...disease duration, more severe motor phenotype, ongoing combined treatment with levodopa and dopamine agonists, and higher levodopa equivalent daily dose. We describe here, to the best of our knowledge, the first case of a woman with PD who developed acute-onset PS caused by chronic subdural hematoma (CSDH).
Case presentation
A 70-year-old woman developed acute-onset lateral flexion of her trunk to the left side while standing, and she was admitted to our hospital. One month before, she had a mild head trauma with loss of consciousness. At 65 years of age, she noticed difficulty with walking and clumsiness with her hands. She was diagnosed as having PD (Hoehn and Yahr stage 2) and levodopa was initiated. Her symptoms were markedly improved. At 67 years of age, she developed orthostatic hypotension and was treated sequentially with fluids, compression stockings, and midodrine. Urgently performed brain computed tomography (CT) showed a CSDH in the right hemisphere resulting in a marked compression of the hemisphere. After surgical evacuation, her PS disappeared. She has fully recovered to her preoperative level of function.
Conclusion
The present case provides a valuable insight, that is, the mesial frontal lobe and its connections from the posterior parietal cortex play crucial roles in maintaining the body schema and in the pathophysiology of PS. This case suggests that CSDH should be considered when clinicians examine acute-onset PS, even in patients with neurodegenerative disorders such as PD. Appropriate patient triage and timely neurosurgical intervention should be considered.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A global pandemic has resulted from the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). To control the spread of ...SARS-CoV-2 infection, several SARS-CoV-2 vaccines have been developed and administered in a wide range of age groups. Messenger ribonucleic acid (mRNA)-based COVID-19 vaccines are the most widely used. We present the case of an 88-year-old woman who was diagnosed with acute disseminated encephalomyelitis (ADEM) following her second mRNA COVID-19 vaccination. She was admitted to hospital with disturbed consciousness (Glasgow Coma Scale E1V1M4) and gaze-evoked nystagmus. Brain magnetic resonance imaging revealed bilateral presence of middle cerebellar peduncle sign. Following steroid pulse therapy, clinical symptoms improved. The occurrence of ADEM following COVID-19 vaccination does not question the importance of vaccination programs during the COVID-19 pandemic. COVID-19 vaccines have been administered to individuals of a wide range of ages, from children to older adults. Thus, ADEM could occur following COVID-19 vaccination at any age, although ADEM is rare in older adults.
•An 88-year-old woman was diagnosed with ADEM following mRNA COVID-19 vaccination.•ADEM may be a rare neurological complication of COVID-19 vaccination.•ADEM is rare in older adults but may occur following COVID-19 vaccination.
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