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21.
Synthetic cannabinoid designer drugs have emerged as drugs of abuse during the last decade, and acute intoxication cases are documented in the scientific literature. Synthetic cannabinoids are extensively metabolized, but our knowledge of the involved enzymes is limited. Here, we investigated the metabolism of N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (AKB-48), a compound identified in herbal blends from 2012 and onwards. We screened for metabolite formation using a panel of nine recombinant cytochrome P450 (CYP) enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4) and compared the formed metabolites to human liver microsomal (HLM) incubations with specific inhibitors against CYP2D6, 2C19, and 3A4, respectively. The data reported here demonstrate CYP3A4 to be the major CYP enzyme responsible for the oxidative metabolism of AKB-48, preferentially performing the oxidation on the adamantyl moiety. Genetic polymorphisms are likely not important with regard to toxicity given the major involvement of CYP3A4. Adverse drug-drug interactions (DDIs) could potentially occur in cases with co-intake of strong CYP3A4 inhibitors, e.g., HIV antivirals and azole antifungal agents.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-015-9788-7) contains supplementary material, which is available to authorized users.KEY WORDS: adamantyl, cytochrome P450, metabolism, metabolites, synthetic cannabinoids 相似文献22.
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Ismael Nilo Lino de Queiroz Ana Luíza Gomes Quinderé José Ariévilo Gurgel Rodrigues Edfranck de Sousa Oliveira Vanderlei Natássia Albuquerque Ribeiro Renata Line da Conceição Rivanor Kátia Alves Ribeiro Chistiane Oliveira Coura Karuza Maria Alves Pereira Hellíada Vasconcelos Chaves Mirna Marques Bezerra Ianna Wivianne Fernandes de Araújo Norma Maria Barros Benevides 《Inflammation research》2015,64(12):971-982
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Chronic airflow obstruction in Fabry's disease 总被引:4,自引:0,他引:4
D M Rosenberg V J Ferrans J D Fulmer B R Line J A Barranger R O Brady R G Crystal 《The American journal of medicine》1980,68(6):898-905
Seven patients with Fabry's disease, an x-linked sphingolipid storage disorder, were evaluated for the presence and extent of airway obstruction. All were found to have significant obstruction to airflow. In addition, evaluation of their airway epithelial cells obtained by bronchoscopy demonstrated that these cells contained inclusion bodies consistent with deposits of ceramide trihexoside, suggesting that part of their functional obstruction to airflow may be secondary to intrinsic airway disease. Although all of the study population had evidence of airflow obstruction, the impairment was much worse in those who smoked, implying that even mild cigarette smoking is particularly hazardous to patients with Fabry's disease. 相似文献
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Anne-Sofie Caroline Jensen Christoffer Polcwiartek Peter Søgaard Rikke Nørmark Mortensen Line Davidsen Mette Aldahl Matilde Alida Eriksen Kristian Kragholm Christian Torp-Pedersen Steen Møller Hansen 《The American journal of medicine》2019,132(2):200-208.e1
Background
Patients with chronic heart failure have vulnerable myocardial function and are susceptible to electrolyte disturbances. In these patients, diuretic treatment is frequently prescribed, though it is known to cause electrolyte disturbances. Therefore, we investigated the association between altered calcium homeostasis and the risk of all-cause mortality in chronic heart failure patients.Methods
From Danish national registries, we identified patients with chronic heart failure with a serum calcium measurement within a minimum 90 days after initiated treatment with both loop diuretics and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Patients were divided into 3 groups according to serum calcium levels, and Cox regression was used to assess the mortality risk of <1.18 mmol/L (hypocalcemia) and >1.32 mmol/L (hypercalcemia) compared with 1.18 mmol/L–1.32 mmol/L (normocalcemia) as reference. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated.Results
Of 2729 patients meeting the inclusion criteria, 32.6% had hypocalcemia, 63.1% normocalcemia, and 4.3% hypercalcemia. The highest mortality risk was present in early deaths (≤30 days), with a HR of 2.22 (95% CI; 1.74-2.82) in hypocalcemic patients and 1.67 (95% CI; 0.96-2.90) in hypercalcemic patients compared with normocalcemic patients. As for late deaths (>30 days), a HR of 1.52 (95% CI; 1.12-2.05) was found for hypocalcemic patients and a HR of 1.87 (95% CI; 1.03-3.41) for hypercalcemic patients compared with normocalcemic patients. In adjusted analyses, hypocalcemia and hypercalcemia remained associated with an increased mortality risk in both the short term (≤30 days) and longer term (>30 days).Conclusion
Altered calcium homeostasis was associated with an increased short-term mortality risk. Almost one-third of all the heart failure patients suffered from hypocalcemia, having a poor prognosis. 相似文献29.
Alexandre R. Espírito Santo John D. Bartlett Carolyn W. Gibson Yong Li Ashok B. Kulkarni Sérgio R. P. Line 《Connective tissue research》2013,54(1):39-52
Dental enamel is the most mineralized tissue of vertebrate organisms. Enamel biosynthesis is initiated by the secretion, processing, and self-assembly of a complex mixture of proteins. The formation of an ordered enamel organic extracellular matrix (ECM) seems be a crucial step for the proper formation of mineral phase. Polarizing microscopy demonstrates that the ordered supramolecular structure of the secretory-stage enamel organic ECM is strongly birefringent. In the present work we analyzed the birefringence of secretory-stage enamel organic ECM in amelogenin (Amelx)- and enamelysin (Mmp20)-deficient mice. Female Amelx+/? animals showed significant reduction in optical retardation values when compared with the Amelx+/+ subgroup (p = 0.0029). The secretory-stage enamel organic ECM of the Amelx?/? subgroup did not exhibit birefringence. The secretory-stage enamel organic ECM of Mmp20?/? mice showed a significant decrease in optical retardation as compared with Mmp20+/+ and Mmp20+/? mice (p = 0.0000). Mmp20+/? and Mmp20+/+ mice exhibited similar birefringence (p = 1.0000). The results presented here support growing evidence for the idea that the birefringence of secretory-stage enamel organic ECM is influenced by the ordered supramolecular organization of its components. 相似文献
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