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1.
Biomed Chromatogr ; : e5955, 2024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38973552

RESUMEN

Ceftriaxone (CTRX) is a commonly used cephalosporin antibiotic. It is suggested that monitoring plasma/serum concentrations is helpful for its safe use. This study aimed to develop and validate an analytical method for measuring CTRX concentrations in human serum according to International Conference on Harmonization guideline M10. Ten microliters of serum sample was purified using a salting-out assisted liquid-liquid extraction procedure with magnesium sulfate. The upper layer was then diluted threefold and analyzed using a liquid chromatography-tandem mass spectrometry-based method with a total run time of 12 min. The linear calibration curve was obtained over the concentration range 5-500 µg/ml. The within-run accuracy varied from 0.2 to 6.5%, and the precision was ≤8.0%. The between-run accuracy and precision ranged from 0.7% to 5.6% and ≤6.4%, respectively. Significant carryover was resolved by injecting four blanks after high-concentration CTRX samples. The recovery rates from spiked serum at low and high concentrations were 44.4 and 43.4%, respectively. Other factors, including selectivity, matrix effects, stability, dilution integrity and reinjection reproducibility also met the acceptance criteria. Serum concentrations in 14 samples obtained from two participants receiving 2 g/day of CTRX were successfully determined using this method.

2.
Artículo en Inglés | MEDLINE | ID: mdl-38970383

RESUMEN

Strigolactones (SLs), plant-derived apocarotenoids, serve dual roles as phytohormones and rhizosphere signaling molecules. While exogenous administration of SLs to plants aids in studying their functions, the metabolic destiny of these administered SLs remains poorly elucidated. Our previous research demonstrated that among synthetic SL GR24 stereoisomers administered to cowpea (Vigna unguiculata), 2'-epi-GR24 undergoes selective reduction at the C-3',4' double bond in its D-ring. In this investigation, we isolated proteins from cowpea roots based on SL reducing activity and identified 12-oxophytodienoate reductase 3 homologs (VuOPR3s) as contributor to this reduction. Enzymatic assays conducted with recombinant proteins revealed that VuOPR3s exhibited a preference for reducing activity toward 2'S-configured SLs, including 2'-epi-GR24. This specificity for 2'S-configured SLs was congruent with that observed for orobanchol produced by cowpea and its stereoisomers. These findings suggest that exogenously administered SLs undergo enzymatic stereoselective reduction, underscoring the importance of considering stereospecificity when interpreting data obtained from SL usage.

3.
Br J Clin Pharmacol ; 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38889797

RESUMEN

AIMS: The aim of the study is to report the clinical and pharmacological observations from a pregnant patient treated with erlotinib in the second and third trimesters of pregnancy. METHODS: Maternal and neonatal blood levels and safety of erlotinib and its metabolites were evaluated. Child development was monitored for 6 years. RESULTS: A 31-year-old woman with stage IV lung adenocarcinoma with EGFR exon19 deletion began treatment with erlotinib 150 mg/day at 17 weeks of gestation. Although foetal growth retardation and oligohydramnios were observed at several times during the pregnancy, treatment was continued due to the severity of the maternal presentation, with ongoing foetal monitoring. The foetus seemed to tolerate and recover well without specific interventions. A healthy baby boy was delivered at 37 weeks gestation. The child grew and developed without any obvious issues. At last follow-up, at age 6 years, he was attending school at a grade appropriate for his age without health or developmental problems. Blood levels of erlotinib were 397-856 ng/mL at 18-37 weeks of gestation and 1190 ng/mL at 8 weeks postpartum. The blood concentration ratios of OSI-413-to-erlotinib ranged from 0.167 to 0.253 at 18-37 weeks of gestation, excluding 24 weeks, and 0.131 at 8 weeks postpartum. The maternal-to-foetal transfer rate of erlotinib, OSI-420 and OSI-413 were 24.5, 34.8 and 20.3%, respectively. CONCLUSION: Erlotinib use during the second and third trimester of pregnancy did not seem to cause any untoward effects on the developing foetus, or any long-lasting effects that could be detected during 6 years of follow-up of the child.

4.
Proc Natl Acad Sci U S A ; 121(26): e2313683121, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38905237

RESUMEN

Strigolactones (SLs) are plant apocarotenoids with diverse roles and structures. Canonical SLs, widespread and characterized by structural variations in their tricyclic lactone (ABC-ring), are classified into two types based on C-ring configurations. The steric C-ring configuration emerges during the BC-ring closure, downstream of the biosynthetic intermediate, carlactonoic acid (CLA). Most plants produce either type of canonical SLs stereoselectively, e.g., tomato (Solanum lycopersicum) yields orobanchol with an α-oriented C-ring. The mechanisms driving SL structural diversification are partially understood, with limited insight into functional implications. Furthermore, the exact molecular mechanism for the stereoselective BC-ring closure reaction is yet to be known. We identified an enzyme, the stereoselective BC-ring-forming factor (SRF), from the dirigent protein (DIR) family, specifically the DIR-f subfamily, whose biochemical function had not been characterized, making it a key enzyme in stereoselective canonical SL biosynthesis with the α-oriented C-ring. We first confirm the precise catalytic function of the tomato cytochrome P450 SlCYP722C, previously shown to be involved in orobanchol biosynthesis [T. Wakabayashi et al., Sci. Adv. 5, eaax9067 (2019)], to convert CLA to 18-oxocarlactonoic acid. We then show that SRF catalyzes the stereoselective BC-ring closure reaction of 18-oxocarlactonoic acid, forming orobanchol. Our methodology combines experimental and computational techniques, including SRF structure prediction and conducting molecular dynamics simulations, suggesting a catalytic mechanism based on the conrotatory 4π-electrocyclic reaction for the stereoselective BC-ring formation in orobanchol. This study sheds light on the molecular basis of how plants produce SLs with specific stereochemistry in a controlled manner.


Asunto(s)
Lactonas , Lactonas/metabolismo , Lactonas/química , Estereoisomerismo , Solanum lycopersicum , Proteínas de Plantas/metabolismo , Proteínas de Plantas/química , Reguladores del Crecimiento de las Plantas/química , Reguladores del Crecimiento de las Plantas/metabolismo
5.
Biol Pharm Bull ; 47(5): 941-945, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38735754

RESUMEN

Hepatitis B virus reactivation (HBV-R) is a serious complication that can occur in patients with resolved HBV infection during cancer chemotherapy. We examined the levels of HBV surface antibody (HBsAb) and HBV core antibody (HBcAb) to assess the incidence of HBV-R in cancer patients including hematopoietic stem cell transplantation (HSCT) and rituximab administration. This retrospective cohort study included 590 patients with resolved HBV infection. The incidence of HBV-R was evaluated 761.5 (range, 90-3898) days after the inititiation of chemotherapy. Of the patients, 13 (2.2%) developed HBV-R after the start of chemotherapy. All 13 patients exhibited lower HBsAb (<100 mIU/mL) levels at baseline. A higher level of HBcAb (≥100 cut off index (C.O.I.)) was a possible risk factor for HBV-R as well as HSCT and rituximab administration. The simultaneous presence of HBsAb <100 mIU/mL and HBcAb ≥100 C.O.I. increased the risk of HBV-R by 18.5%. Patients treated with rituximab were at a higher risk of HBV-R (18.4%) despite having HBcAb <100 C.O.I. Our results suggest that assessment of HBsAb and HBcAb levels prior to the chemotherapy is important for identifying patients at high risk of HBV-R, especially in solid cancers without HSCT and rituximab administration.


Asunto(s)
Anticuerpos contra la Hepatitis B , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B , Hepatitis B , Rituximab , Activación Viral , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anticuerpos contra la Hepatitis B/sangre , Anticuerpos contra la Hepatitis B/inmunología , Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/fisiología , Activación Viral/efectos de los fármacos , Rituximab/uso terapéutico , Rituximab/efectos adversos , Adulto , Anciano , Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Adulto Joven , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Antígenos del Núcleo de la Hepatitis B/inmunología , Antígenos del Núcleo de la Hepatitis B/sangre , Anciano de 80 o más Años , Adolescente
6.
Front Plant Sci ; 15: 1392212, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38699535

RESUMEN

Strigolactones (SLs), a class of plant apocarotenoids, serve dual roles as rhizosphere-signaling molecules and plant hormones. Orobanchol, a major naturally occurring SL, along with its various derivatives, has been detected in the root exudates of plants of the Fabaceae family. Medicaol, fabacyl acetate, and orobanchyl acetate were identified in the root exudates of barrel medic (Medicago truncatula), pea (Pisum sativum), and cowpea (Vigna unguiculata), respectively. Although the biosynthetic pathway leading to orobanchol production has been elucidated, the biosynthetic pathways of the orobanchol derivatives have not yet been fully elucidated. Here, we report the identification of 2-oxoglutarate-dependent dioxygenases (DOXs) and BAHD acyltransferases responsible for converting orobanchol to these derivatives in Fabaceae plants. First, the metabolic pathways downstream of orobanchol were analyzed using substrate feeding experiments. Prohexadione, an inhibitor of DOX inhibits the conversion of orobanchol to medicaol in barrel medic. The DOX inhibitor also reduced the formation of fabacyl acetate and fabacol, a precursor of fabacyl acetate, in pea. Subsequently, we utilized a dataset based on comparative transcriptome analysis to select a candidate gene encoding DOX for medicaol synthase in barrel medic. Recombinant proteins of the gene converted orobanchol to medicaol. The candidate genes encoding DOX and BAHD acyltransferase for fabacol synthase and fabacol acetyltransferase, respectively, were selected by co-expression analysis in pea. The recombinant proteins of the candidate genes converted orobanchol to fabacol and acetylated fabacol. Furthermore, fabacol acetyltransferase and its homolog in cowpea acetylated orobanchol. The kinetics and substrate specificity analyses revealed high affinity and strict recognition of the substrates of the identified enzymes. These findings shed light on the molecular mechanisms underlying the structural diversity of SLs.

8.
Clin Pharmacol Ther ; 115(5): 1015-1024, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38093601

RESUMEN

Although various lipophilic drugs are bound to lipoproteins, lipoprotein binding in plasma is not usually considered in current physiologically-based pharmacokinetic (PBPK) models. Amiodarone is extensively bound to serum triglyceride-rich lipoproteins. Total plasma amiodarone concentration, which is the sum of both unbound and bound concentrations, increases with increasing serum triglyceride levels. We investigated the impact of lipoprotein binding on amiodarone pharmacokinetics using PBPK modeling and simulations. An amiodarone PBPK model that incorporates plasma lipoprotein binding (LPP model) was developed based on the correlation between serum triglyceride levels and lipoprotein-bound amiodarone. The predicted unbound fraction of amiodarone in plasma and systemic clearance in the LPP and base models (with albumin binding only) were similar, but the coefficients of variation for the LPP model were greater than those for the base model and were closer to the observed data. The total plasma amiodarone concentration predicted using the LPP model increased with higher levels of plasma lipoprotein binding and serum albumin. In contrast, changes in plasma lipoprotein binding and serum albumin levels did not influence the predicted unbound plasma amiodarone concentration at steady-state. This study demonstrates that incorporating plasma lipoprotein binding into a PBPK model improves the accuracy of predicting interindividual variabilities in amiodarone clearance by more reliably predicting the interindividual variability in the plasma unbound fraction of amiodarone. Plasma lipoprotein binding should be considered in PBPK modeling and simulations for lipoprotein-associated drugs if there is available information on the relationship between plasma lipoprotein binding and hyperlipidemia.


Asunto(s)
Amiodarona , Humanos , Modelos Biológicos , Lipoproteínas , Simulación por Computador , Albúmina Sérica , Triglicéridos
9.
J Pharm Health Care Sci ; 9(1): 52, 2023 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-38115129

RESUMEN

BACKGROUND: Nucleoside analogues (NAs) such as entecavir are required for at least 12 months when patients with resolved hepatitis B virus (HBV) infection develop HBV reactivation. Entecavir treatment does not always achieve hepatitis B surface antigen (HBsAg) seroconversion. The cessation of NA for HBV reactivation sometimes causes HBV rebound. The impact of hepatitis B core-related antigen (HBcrAg) on predicting HBV rebound is controversial. CASE PRESENTATION: A 67-year-old woman with resolved HBV infection received rituximab for post-transplant lymphoproliferative disorder after peripheral blood stem cell transplantation. Since she tested positive for HBV-DNA after the first rituximab therapy (day 0), entecavir treatment was started. Because the HBV-DNA test became negative and her liver function had been normal, entecavir was terminated on day 376. According to the retrospective measurements, HBcrAg remained positive while the HBV-DNA level was undetectable. One hundred forty-one days after entecavir cessation, the HBV-DNA turned positive again, suggesting HBV rebound (day 517). Her liver function deteriorated and HBV infection worsened, even though entecavir treatment was resumed on day 615. On the contrary, hepatitis B surface antibody levels increased after the rebound, resulting in HBsAg seroconversion with HBcrAg and HBV-DNA levels undetectable. HBV reactivation has not been detected after the second entecavir cessation, and both HBcrAg and HBV-DNA levels remained undetectable. DISCUSSION AND CONCLUSIONS: This case suggests that NA cessation induced-HBV rebound achieved HBsAg seroconversion under the guidance of a hepatologist. Since HBcrAg had been detectable while HBV-DNA was undetectable, HBcrAg may be an index for predicting HBV rebound resulting in HBsAg seroconversion as well as other conventional laboratory tests. Prospective measuring HBcrAg is required to confirm this case report.

10.
Cancer Chemother Pharmacol ; 92(4): 271-278, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37458784

RESUMEN

PURPOSE: Considerable amounts of injected immunoglobulin G-based therapeutic monoclonal antibodies, such as ramucirumab, are distributed into ascites. This study aimed to examine the effect of massive ascites on ramucirumab pharmacokinetics in patients with gastrointestinal cancers. METHODS: Population pharmacokinetic analysis of ramucirumab was performed using data on serum ramucirumab concentrations of 52 patients with gastrointestinal cancers, including 8 patients with massive ascites. The Bayesian method using the final population pharmacokinetic model was utilized to estimate trough ramucirumab concentrations after the first dose and at steady state. RESULTS: Population pharmacokinetic analysis revealed that massive ascites as well as body weight were influencing factors for ramucirumab clearance. The estimated ramucirumab clearance was significantly higher in patients with massive ascites than in those with no/mild ascites (0.020 ± 0.004 versus 0.013 ± 0.004 L/h, P < 0.001). The estimated trough ramucirumab concentrations were significantly lower in patients with massive ascites than in those with no/mild ascites after the first dose (26.4 ± 6.8 versus 36.1 ± 7.1 µg/mL, P < 0.001) and at steady state (41.4 ± 16.3 versus 65.9 ± 18.0 µg/mL, P < 0.001). CONCLUSION: In the present study, the presence of massive ascites affected the pharmacokinetics of ramucirumab in patients with gastrointestinal cancers. Our results suggest that dose optimization of ramucirumab may be necessary in patients with massive ascites due to higher ramucirumab clearance.


Asunto(s)
Ascitis , Neoplasias Gastrointestinales , Humanos , Ascitis/tratamiento farmacológico , Teorema de Bayes , Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales/efectos adversos , Neoplasias Gastrointestinales/tratamiento farmacológico , Ramucirumab
11.
Langenbecks Arch Surg ; 408(1): 189, 2023 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-37166568

RESUMEN

PURPOSE: Necrotizing soft-tissue infection (NSTI) is a surgical emergency associated with high mortality. This study primarily aimed to identify the factors associated with in-hospital mortality due to NSTI in the extremities at a single institution. Secondarily, we aimed to clarify the effectiveness of the optimal combination of hyperbaric oxygen therapy (HBOT) and surgery for NSTI treatment. STUDY DESIGN: Retrospective observational study. METHODS: This study included all patients newly diagnosed with NSTI in the extremity from 2003 to 2021 in our hospital. Factors associated with mortality, including patient's characteristics, duration from onset to hospitalization, NSTI type, and clinical data at the initial visit; acute disseminated intravascular coagulation (DIC), laboratory risk indicator for necrotizing fasciitis score, and sequential organ failure assessment score; treatment, initial surgery, surgery times, amputation, HBOT, combined surgery with HBOT, and clinical outcomes; amputation rate, mortality rate, and hospitalization duration were examined. RESULTS: A total of 37 cases were treated for NSTIs. The median age was 64 years (range: 22-86). Five cases (13.5%) died during hospitalization. Ten patients were diagnosed with DIC at the initial visit, of whom four died. HBOT combined with surgery was performed in 23 cases, and 16 cases underwent multiple surgeries. Factors associated with mortality included DIC (p = 0.015, 95% confidence interval [CI]: 0.015-0.633) and multiple surgeries combined with HBOT (p = 0.028, 95% CI: 1.302-95.418). CONCLUSION: This study demonstrates that DIC at the initial visit is associated with mortality in extremity NSTI. Additionally, HBOT might improve prognosis when combined with multiple surgeries.


Asunto(s)
Fascitis Necrotizante , Infecciones de los Tejidos Blandos , Humanos , Persona de Mediana Edad , Infecciones de los Tejidos Blandos/cirugía , Infecciones de los Tejidos Blandos/complicaciones , Fascitis Necrotizante/cirugía , Fascitis Necrotizante/complicaciones , Pronóstico , Hospitalización , Estudios Retrospectivos , Factores de Riesgo , Extremidades
12.
J Nat Med ; 77(3): 476-488, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36854954

RESUMEN

Ephedrae Herba is among the important crude drugs prescribed in Kampo medicine for the treatment of cold, flue, rhinitis, nasal congestion, cough, and asthma. The active ingredients of Ephedrae Herba, ephedrine (E) and pseudoephedrine (PE), are potent sympathomimetic compounds that stimulate α-, ß1-, and ß2-adrenoceptors resulting in dilatation and alleviation of nasal mucosal hyperemia. Hypertension, palpitations, insomnia, and dysuria are the main adverse effects of E and PE, which can be avoided by determining the actual contents of these alkaloids in Kampo extracts containing Ephedrae Herba. However, the extraction efficiencies of E and PE from Ephedrae Herba contained in Kampo formulas in combination with other crude drugs remain unknown. Therefore, we comprehensively determined the E and PE contents of 34 Kampo extracts containing Ephedrae Herba used clinically in Japan. The E and PE contents per daily dosage in Kampo extracts were generally proportional to the compounding amount of Ephedrae Herba. In contrast, the extraction efficiencies of E or PE were not constant and not influenced by the pH of the extracts. We assume that the extraction efficiencies of E and PE may be independently affected by other constituent crude drugs. Thus, it is necessary to investigate the cause and mechanism in the future. In conclusion, these results show that the E and PE content of each Kampo formulation can be estimated from the compounding amount of Ephedrae Herba. Therefore, the amount of Ephedrae Herba should be carefully considered to ensure the safe use of Kampo formulations containing Ephedrae Herba.


Asunto(s)
Medicamentos Herbarios Chinos , Efedrina , Seudoefedrina , Medicina Kampo , Japón
13.
Cancer Chemother Pharmacol ; 90(5): 421-426, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36180639

RESUMEN

BACKGROUND: Therapeutic monoclonal antibodies, including ramucirumab and nivolumab, are used to treat advanced gastric cancer (AGC). Malignant ascites is often accompanied by peritoneal metastasis in AGC patients. However, the distribution of therapeutic monoclonal antibodies into ascites has yet to be adequately investigated. METHODS: We determined serum and ascites concentrations of ramucirumab or nivolumab and total IgG in three AGC patients with massive ascites. When serum and ascites samples were obtained on the same day, the ascites-to-serum ratio (A/S ratio) of the concentration of monoclonal antibodies was evaluated. The relationship between time after last infusion and the A/S ratio of therapeutic monoclonal antibodies was examined using 15 datasets from the present study and the literature. RESULTS: Ramucirumab and nivolumab were detected in massive ascites at considerable amounts (A/S ratios of 0.24-0.35 for ramucirumab and 0.17-0.55 for nivolumab). A positive correlation was detected between the A/S ratios of the therapeutic monoclonal antibodies and the time after last infusion (r = 0.747). Removal of ascites using paracentesis eliminated at least 15.3%-30.3% and 5.2-27.4% of the injected ramucirumab and nivolumab, respectively. Endogenous IgG, as well as therapeutic monoclonal antibodies, were distributed into ascites; the A/S ratios for IgG were 0.22-0.45. CONCLUSION: Our results suggest that therapeutic monoclonal antibodies, including ramucirumab and nivolumab, are distributed into massive ascites in AGC patients concomitantly with endogenous IgG. In these patients, retention of ascites and its removal may result in decreased systemic drug exposure to ramucirumab and nivolumab.


Asunto(s)
Antineoplásicos Inmunológicos , Neoplasias Peritoneales , Neoplasias Gástricas , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ascitis/tratamiento farmacológico , Humanos , Inmunoglobulina G/uso terapéutico , Nivolumab/uso terapéutico , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología
14.
Contemp Clin Trials Commun ; 29: 100967, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35967517

RESUMEN

Background: It is unclear which laxatives are appropriate to prevent opioid-induced constipation (OIC). This study will evaluate whether prophylactic use of naldemedine prevents OIC in patients with cancer who start opioid administration. Methods: This study is a multicenter, double-blinded, randomized, placebo-controlled trial. Patients who meet the eligibility criteria and give consent will be randomly assigned to the naldemedine or placebo group. Both groups will take each drug once a day after breakfast for 14 days. Results: The primary endpoint is the proportion of patients with a Bowel Function Index of less than 28.8 on Day 14. The secondary endpoints include assessment scales of the impact of constipation on comprehensive quality of life. Conclusions: This is the first study proposed to assess the superiority of naldemedine over placebo in the prevention of OIC. If naldemedine is found to be effective in reducing OIC compared with the placebo, it will be regarded as a new standard for OIC prophylaxis at opioid initiation. Trial registration: jRCT identifier: jRCTs031200397. Registered March 5, 2021, https://rctportal.niph.go.jp/en/detail?trial_id=jRCTs031200397.

15.
Clin Transl Sci ; 15(3): 771-781, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34786846

RESUMEN

Amiodarone and its main metabolite, desethylamiodarone (DEA), are highly distributed to serum lipoproteins such as very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), which are the carriers of triglyceride and cholesterol. This study aimed to investigate the association of serum concentrations of amiodarone and DEA with the levels of serum lipids in terms of drug distribution to lipoprotein fractions in patients with hyperlipidemia. Total serum concentrations of amiodarone and DEA were examined in 116 patients receiving amiodarone for tachyarrhythmias. The concentration-to-dose (C/D) ratio of amiodarone positively correlated with the level of serum triglyceride (rs  = 0.541, p < 0.001) and was higher in the hypertriglyceridemic state than in normotriglyceridemic state (479 ± 211 vs. 320 ± 161, p < 0.001). No correlation was found between the C/D ratio of DEA and serum triglyceride levels (rs  = 0.272), although higher values were observed in the hypertriglyceridemic state (322 ± 125 vs. 285 ± 143, p < 0.001). In the hypertriglyceridemic state, the distribution of amiodarone increased in LDL/VLDL fraction and decreased in high-density lipoprotein and albumin fractions. The ratio of serum amiodarone to serum DEA, a metabolic ratio of amiodarone, positively correlated with serum triglyceride levels (rs  = 0.572, p < 0.001) and was higher in the hypertriglyceridemic state, suggesting that amiodarone metabolism decreased in hyperlipidemia. The results of this study reveal that serum concentrations of amiodarone increase in the hypertriglyceridemic state through the increased lipoprotein-binding and decreased metabolism of amiodarone.


Asunto(s)
Amiodarona , Hiperlipidemias , Amiodarona/efectos adversos , Humanos , Lipoproteínas , Lipoproteínas LDL , Lipoproteínas VLDL , Triglicéridos/metabolismo
16.
Front Nutr ; 8: 719197, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34604277

RESUMEN

Licorice, the dried root or stolon of Glycyrrhiza glabra or G. ularensis, is commonly used worldwide as a food sweetener or crude drug. Its major ingredient is glycyrrhizin. Hypokalemia or pseudoaldosteronism (PsA) is one of the most frequent side effects of licorice intake. Glycyrrhizin metabolites inhibit type 2 11ß-hydroxysteroid dehydrogenase (11ßHSD2), which decomposes cortisol into inactive cortisone in the distal nephron, thereby inducing mineralocorticoid receptor activity. Among the several reported glycyrrhizin-metabolites, 18ß-glycyrrhetyl-3-O-sulfate is the major compound found in humans after licorice consumption, followed by glycyrrhetinic acid. These metabolites are highly bound to albumin in blood circulation and are predominantly excreted into bile via multidrug resistance-associated protein 2 (Mrp2). High dosage and long-term use of licorice are constitutional risk factors for PsA. Orally administered glycyrrhizin is effectively hydrolyzed to glycyrrhetinic acid by the intestinal bacteria in constipated patients, which enhances the bioavailability of glycyrrhizin metabolites. Under hypoalbuminemic conditions, the unbound metabolite fractions can reach 11ßHSD2 at the distal nephron. Hyper direct-bilirubin could be a surrogate marker of Mrp2 dysfunction, which results in metabolite accumulation. Older age is associated with reduced 11ßHSD2 function, and several concomitant medications, such as diuretics, have been reported to affect the phenotype. This review summarizes several factors related to licorice-induced PsA, including daily dosage, long-term use, constipation, hypoalbuminemia, hyper direct-bilirubin, older age, and concomitant medications.

18.
J Clin Med ; 10(17)2021 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-34501411

RESUMEN

Kidney transplant recipients with tacrolimus-based immunosuppressive therapy are often treated with proton-pump inhibitors (PPIs) to prevent gastric ulcer complications. Vonoprazan, a potassium-competitive acid blocker, is a novel PPI possessing different metabolic pathways from conventional PPIs (e.g., omeprazole, lansoprazole and rabeprazole). However, no data are available on the change in blood concentration of tacrolimus after switching rabeprazole, a conventional PPI, to vonoprazan coadministration in the initial period of post-transplantation. This is a retrospective study of 18 kidney transplant recipients. The blood concentration and the concentration to dose (C/D) ratio of tacrolimus were compared before and after switching from rabeprazole to vonoprazan. Impacts of CYP2C19 and CYP3A5 genetic polymorphisms on the drug-drug interaction were also examined. The median (range) trough concentration of tacrolimus was significantly increased from 5.2 (3.6-7.4) to 8.1 (6.1-11.7) ng/mL (p < 0.0005) after switching from rabeprazole to vonoprazan. The C/D ratio of tacrolimus was also significantly increased from 38.1 (16.5-138.1) to 48.9 (26.2-207.2) (p < 0.0005). The percent changes of tacrolimus concentrations and C/D were 65.8% and 41.8%, respectively. CYP2C19 and CYP3A5 genetic polymorphisms did not affect the change in concentration and C/D ratio of tacrolimus. The present study indicates that vonoprazan coadministration increases the tacrolimus concentration regardless of CYP2C19 or CYP3A5 genetic polymorphisms. Thus, frequent monitoring of blood tacrolimus concentration is required when vonoprazan is introduced as an intensive gastric acid blocker in the early phase of post-transplantation.

19.
J Pain Symptom Manage ; 62(3): 537-544, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33516927

RESUMEN

CONTEXT: Oral mucositis (OM) pain due to anticancer chemo- and radiotherapy has a very negative impact on patient quality of life. However, no high-quality studies have been performed regarding the analgesic efficacy of indomethacin (IM) oral spray for OM pain. OBJECTIVES: This randomized, placebo-controlled, double-blind trial aimed to evaluate the analgesic efficacy of IM oral spray for OM pain due to anticancer chemo- and radiotherapy. METHODS: From July 2015 to December 2016, we enrolled adult cancer patients with OM pain that was due to anticancer chemo- or radiotherapy and was rated 4 or higher on Brief Pain Inventory (BPI) Item 5. Patients were randomly assigned in a 1:1 ratio to receive either IM oral spray or placebo. The primary endpoint was the change in the BPI Item 6 ("current pain") score from before to 30 minutes after treatment. Secondary endpoints were the areas under the curves of BPI Item 6 at 15, 60, 120, 180, and 240 minutes after treatment; five items related to meals and conversation from the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire, Head and Neck Module 35; the Clinical Global Impressions-Improvement (CGI-I) scale; and adverse events. RESULTS: A total of 60 patients were assigned to receive IM oral spray (n = 33) or placebo spray (n = 27). The average change in the BPI item 6 score from before to 30 minutes after treatment was -1.85 (95% confidence interval: -2.37 to -1.32) in the IM spray group and -0.59 (-1.02 to -0.16) in the placebo group, indicating a significant difference (-1.26, -1.94 to -0.57, P < 0.01). The pain improvement persisted for 180 minutes. The intergroup differences in ability to drink liquids, ease in conversing, and CGI-I were all significant (P = 0.03, P = 0.02, and P < 0.01, respectively). No serious adverse events were reported. CONCLUSION: IM oral spray alleviated short-term OM pain due to anticancer chemo- and radiotherapy, and may reduce the difficulty in eating meals.


Asunto(s)
Neoplasias de Cabeza y Cuello , Estomatitis , Adulto , Método Doble Ciego , Humanos , Indometacina , Vaporizadores Orales , Dolor/tratamiento farmacológico , Dolor/etiología , Calidad de Vida , Estomatitis/tratamiento farmacológico , Estomatitis/etiología
20.
Biomed Chromatogr ; 35(5): e5049, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33314287

RESUMEN

Eltrombopag, a thrombopoietin receptor agonist, is used for the treatment of idiopathic thrombocytopenic purpura (ITP) and aplastic anemia. We developed a HPLC assay for the determination of serum eltrombopag concentration in ITP patients. An aliquot of a serum sample spiked with diclofenac as the internal standard (IS) was treated with acetonitrile to precipitate the proteins. Eltrombopag and the IS were separated on an octadecylsilyl silica-gel column using a mobile phase consisting of 10 mM 1-pentanesulfonic acid sodium salt, acetonitrile, and acetic acid. The detection wavelength was set at 265 nm. The calibration curve was linear at the concentration range of 0.15-12.5 µg/mL for eltrombopag (r = 0.9987). The recoveries of eltrombopag from the serum samples were greater than 95.9% with coefficients of variation (CVs) being less than 2.8%. The CVs for the intra-day and inter-day assays were 1.9-11.8% and 1.0-11.8%, respectively. This assay method could be used for therapeutic drug monitoring of eltrombopag in ITP patients.


Asunto(s)
Benzoatos/sangre , Cromatografía Líquida de Alta Presión/métodos , Hidrazinas/sangre , Pirazoles/sangre , Receptores de Trombopoyetina/antagonistas & inhibidores , Benzoatos/administración & dosificación , Diclofenaco/normas , Monitoreo de Drogas , Humanos , Hidrazinas/administración & dosificación , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Pirazoles/administración & dosificación , Estándares de Referencia
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