The Distribution of Quetiapine and 7-Hydroxyquetiapine in Guinea Pig Hair Roots and Shafts after Repeated Administration: Exploration of the Mechanism of Drug Entry and Retention in Hair

2020 ◽  
Author(s):  
Jiao-Jiao Ji ◽  
Hui Yan ◽  
Ping Xiang ◽  
Xin Wang ◽  
Min Shen
Keyword(s):  
Guinea Pig ◽  
Repeated Administration ◽  
Hair Shaft ◽  
High Dose ◽  
Hair Root ◽  
Segmental Analysis ◽  
Drug Concentrations ◽  
Hair Roots ◽  
Hair Shafts ◽  
Drug Entry

Abstract This study investigated the distribution of quetiapine and 7-hydroxyquetiapine in guinea pig hair roots and shafts after five repeated intragastric administrations at three doses (5, 10 and 25 mg/kg) by segmental analysis to explore the mechanism of drug entry and retention in hair. Hair root samples were collected after 7, 10, 14, 21, 28 and 35 d in area A after the first dose, and a hair shaft was plucked 35 d after the first dose. The maximum concentrations of quetiapine in hair roots in the low-, medium- and high-dose groups occurred at 50, 74 and 98 h after the first administration, and the maximum concentrations were 0.71 ng/mg (range: 0.54–0.84 ng/mg), 6.72 ng/mg (range: 4.59–9.75 ng/mg) and 12.72 ng/mg (range: 10.74–15.76 ng/mg), respectively. The maximum concentrations of 7-hydroxyquetiapine in the low-, medium- and high-dose groups were 0.67 ng/mg (0.23–1.15 ng/mg), 1.07 ng/mg (0.44–1.19 ng/mg) and 3.92 ng/mg (0.656.14 ng/mg), respectively, at 26 h. The maximum concentrations of quetiapine and 7-hydroxyquetiapine in hair roots were significantly positively correlated with the dose (n = 18; r2 = 0.84; P < 0.0001 for quetiapine and n = 18; r2 = 0.61; P = 0.0001 for 7-hydroxyquetiapine). The concentrations of quetiapine and 7-hydroxyquetiapine in hair roots were higher than those in hair shafts 10 d after administration, indicating drug and metabolite entry into the hair through the roots in the first few days after administration. The highest concentrations of quetiapine in the hair shaft in the low-, medium- and high-dose groups were found at the hair ends, and 7-hydroxyquetiapine in the hair shaft showed no obvious peak concentration. Combined with previous studies, we think, by analyzing the drug concentrations in the hair roots and shaft, that the most important way for drugs to enter into and be retained in hair is that the drug enters the hair through the blood circulation from hair root, then spreads and redistributes as the hair grows.

scholarly journals A Pediatric Case of Sirolimus-Associated Pneumonitis After Kidney Transplantation

2020 ◽  
Vol 25 (5) ◽  
pp. 459-464 ◽  
Author(s):  
Jelte Kelchtermans ◽  
Jessica Chang ◽  
Wendy Glaberson ◽  
Marissa DeFreitas ◽  
Monica Alba-Sandoval ◽  
...  
Keyword(s):  
Transplant Recipient ◽  
Pulmonary Toxicity ◽  
Pediatric Population ◽  
Kidney Transplant Recipient ◽  
Ventilatory Support ◽  
Solid Organ Transplantation ◽  
Adult Patients ◽  
High Dose ◽  
Solid Organ ◽  
Drug Concentrations

Sirolimus is an immunosuppressive medication often used in solid organ transplantation. It has been associated with severe side effects, including pulmonary toxicity. In adult patients, a single center study found that 14% of those treated with sirolimus developed pulmonary pneumonitis; however, the incidence in the pediatric population is not known. Most reports in adult patients indicate that elevated drug concentrations and a prolonged duration of use are associated with pulmonary toxicity. We report a case of a 17-year-old male kidney transplant recipient who developed rapid-onset respiratory failure, necessitating mechanical ventilation and acute renal replacement therapy for ultrafiltration secondary to sirolimus-induced pneumonitis. He had been treated for acute rejection with corticosteroids 17 days prior to the development of pneumonitis. His symptoms developed within 1 week of initiation of sirolimus and with a serum concentration of 1.1 ng/mL. Sirolimus was discontinued, and, following aggressive diuresis and ventilatory support, his respiratory status returned to baseline. Sirolimus-induced pneumonitis is an important diagnosis to be considered in any transplant recipient receiving sirolimus with new onset fever, cough, or dyspnea without an identifiable source, especially if there is a preceding history of treatment with high-dose corticosteroids.

scholarly journals Concentration of meropenem in patients with sepsis and acute kidney injury before and after initiation of continuous renal replacement therapy: a prospective observational trial

2020 ◽  
Vol 72 (1) ◽  
pp. 147-155 ◽  
Author(s):  
Ilona Nowak-Kózka ◽  
Kamil J. Polok ◽  
Jacek Górka ◽  
Jakub Fronczek ◽  
Anna Gielicz ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Kidney Injury ◽  
Regional Citrate Anticoagulation ◽  
High Dose ◽  
Prolonged Infusion ◽  
Time Points ◽  
Drug Concentrations ◽  
Before And After

Abstract Background The effect of renal replacement therapy on drug concentrations in patients with sepsis has not been fully elucidated because the pharmacokinetic properties of many antimicrobials are influenced by both pathophysiological and treatment-related factors. The aim of this study was to determine meropenem concentrations in patients with sepsis before and after the initiation of continuous venovenous hemodialysis with regional citrate anticoagulation (RCA-CVVHD). Methods The study included 15 critically ill patients undergoing RCA-CVVHD due to sepsis-induced acute kidney injury. All participants received 2 g of meropenem every 8 h in a prolonged infusion lasting 3 h. Meropenem concentrations were measured in blood plasma using high-performance liquid chromatography coupled with tandem mass spectrometry. Blood samples were obtained at six-time points prior to and at six-time points after introducing RCA-CVVHD. Results The median APACHE IV and SOFA scores on admission were 118 points (interquartile range [IQR] 97–134 points) and 19.5 points (IQR 18–21 points), respectively. There were no significant differences in the plasma concentrations of meropenem measured directly before RCA-CVVHD and during the first 450 min of the procedure. The drug concentration reached its peak 2 h after initiating the infusion and then steadily declined. Conclusions The concentration of high-dose meropenem (2 g every 8 h) administered in a prolonged infusion was similar before and after the introduction of RCA-CVVHD in patients with sepsis who developed acute kidney injury.

scholarly journals Comparative Dispositions of Ofloxacin in Human Head, Axillary, and Pubic Hairs

1998 ◽  
Vol 42 (5) ◽  
pp. 1298-1302 ◽  
Author(s):  
Kazuhiro Kosuge ◽  
Toshihiko Uematsu ◽  
Sei-Ichi Araki ◽  
Hiroyuki Matsuno ◽  
Kyoichi Ohashi ◽  
...  
Keyword(s):  
Growth Rate ◽  
Human Head ◽  
Pubic Hair ◽  
Hair Shaft ◽  
The Other ◽  
Healthy Male ◽  
Head Hair ◽  
Hair Type ◽  
Axillary Hair ◽  
Hair Shafts

ABSTRACT The distribution of ofloxacin (OFLX) along the shaft of each of three hair types, i.e., head, axillary and pubic, was investigated and compared among five healthy male volunteers 1 to 4 months after ingestion of OFLX for 1 or 2 days (total dose, 200 or 600 mg). Five strands of each hair type were sectioned together into successive 0.5-cm lengths starting from the dermal end, over a length of ≤6 cm, and the OFLX concentration in each hair section was measured by high-pressure liquid chromatography with fluorescence detection. The distribution of OFLX along the head hair shaft was narrow, having a single peak even 3 to 4 months after administration, suggesting a rather uniform growth rate among hair strands. On the other hand, the OFLX distribution along axillary or pubic hair shafts tended to be broad, even having two apparent peaks, and the growth rate did not seem uniform. Since axillary hair seemed to stop growing after having gained a length of ≤4 to 5 cm, it was suggested to enter a resting stage after the growth of ≤3 cm over the 2 to 4 months after OFLX incorporation. These findings indicate that head hair is the most suitable for analysis of individual drug use and the larger growth rate and cycle stage variabilities of strands of the other types of hair should be taken into account.

scholarly journals Dietary Intervention Accelerates NASH Resolution Depending on Inflammatory Status with Minor Additive Effects on Hepatic Injury by Vitamin E Supplementation

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 808
Author(s):  
Julie Hviid Klaebel ◽  
Günaj Rakipovski ◽  
Birgitte Andersen ◽  
Jens Lykkesfeldt ◽  
Pernille Tveden-Nyborg
Keyword(s):  
Vitamin E ◽  
Guinea Pig ◽  
Lipid Accumulation ◽  
Guinea Pigs ◽  
Dietary Intervention ◽  
Liver Weight ◽  
High Dose ◽  
Chow Diet ◽  
Lifestyle Modifications ◽  
Inflammatory Status

Despite the lack of effective pharmacotherapy against nonalcoholic steatohepatitis (NASH) and liver fibrosis, vitamin E (vitE) supplementation and lifestyle modifications are recommended for the management of NASH due to promising clinical results. We recently reported a positive effect of supplementation with 800 IU vitE and atorvastatin on NASH resolution in guinea pigs. In the present study, we investigated the effect of high-dose vitE therapy combined with dietary intervention against progressive NASH and advanced fibrosis in the guinea pig model. Sixty-six guinea pigs received either high-fat (HF) or standard guinea pig chow diet (Control) for 25 weeks. Prior to eight weeks of intervention, HF animals were allocated into groups; dietary intervention (Chow) or dietary intervention with 2000 IU/d vitE supplementation (CvitE). Both Chow and CvitE reduced dyslipidemia, hepatic lipid accumulation and liver weight (p < 0.05), while CvitE further decreased hepatocellular ballooning (p < 0.05). Subanalyses of individual responses within intervention groups showed significant correlation between the hepatic hallmarks of NASH and lipid accumulation vs. inflammatory state (p < 0.05). Collectively, our results indicate that individual differences in sensitivity towards intervention and inflammatory status determine the potential beneficial effect of dietary intervention and high-dose vitE supplementation. Moreover, the study suggests that inflammation is a primary target in NASH treatment.

scholarly journals Effects of Portulaca Oleracea Extract on Acute Alcoholic Liver Injury of Rats

Molecules ◽  
2019 ◽  
Vol 24 (16) ◽  
pp. 2887 ◽  
Author(s):  
Jing-Yi Qiao ◽  
Han-Wei Li ◽  
Fu-Gang Liu ◽  
Yu-Cheng Li ◽  
Shuo Tian ◽  
...  
Keyword(s):  
Liver Injury ◽  
High Performance ◽  
Chemical Constituents ◽  
Elevated Serum ◽  
Repeated Administration ◽  
Portulaca Oleracea ◽  
High Dose ◽  
Protective Effects ◽  
Alcoholic Liver Injury ◽  
Lipid Metabolism Disorder

The present study was envisaged to investigate the chemical constituents and the intervention effects of Portulaca oleracea extract (POE) on acute alcoholic liver injury of rats. The chemical composition of POE was detected by high performance liquid chromatography (HPLC). Sixty male Wistar rats were divided into 6 groups: Normal control (NC) group, acute alcoholic liver injury model group (ALI), low, medium and high dose of POE (25, 50, 100 mg/kg) groups and bifendate (BF, 3.75 mg/kg) group. Each group was given by intragastrical administration for 7 days. Alcoholic liver injury was induced in the experimental model by administering 50% ethanol at 8 mL/kg and repeated administration after 6 h, for a period of 7 days. The results showed that pretreatment with POE significantly reduced the ethanol-elevated serum level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and triglyceride (TG). The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) in liver were enhanced followed by administration of POE, while the content of nitric oxide (NO) and malondialdehyde (MDA) was found to decrease. Hepatic content of tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) was also reduced by POE treatment. These results indicated that POE could increase the antioxidant capacity and relieve the inflammatory injury of the liver cells induced by ethanol. Meanwhile, in our study, POE reduced the expression of miR-122, acetyl coenzyme A carboxylase (ACC) 1 mRNA and protein and increased the expression of lipoprotein lipase (LPL) mRNA and protein in liver, which indicated that POE could improve the lipid metabolism disorder induced by ethanol. Our findings suggested that POE had protective effects on acute alcoholic liver injury of rats.

Segmental Analysis of R/S-Methamphetamine and R/S-Amphetamine in Abusers’ Head Hair

2020 ◽  
Vol 44 (6) ◽  
pp. 596-600
Author(s):  
Ting Wang ◽  
Baohua Shen ◽  
Hejian Wu ◽  
Jun Gu ◽  
Min Shen ◽  
...  
Keyword(s):  
Hair Analysis ◽  
Gradual Increase ◽  
Drug Dose ◽  
Segmental Analysis ◽  
Head Hair ◽  
Drug Concentrations ◽  
Frequency Of Use ◽  
Hair Samples ◽  
Hair Matrix ◽  
Segmental Hair Analysis

Abstract In this study, the relationships between the concentrations of R/S-methamphetamine (MA) and its metabolite R/S-amphetamine (AP), the AP/MA ratio in hair samples, and MA dependence were investigated by performing segmental hair analysis in MA users. Authentic hair samples collected from 10 chronic MA abusers were cut into 1-cm sections (a total of 120 segments). The concentrations of MA and AM enantiomers were quantitatively measured by the LC–MS-MS method. The S-MA concentrations ranged from 1.17 to 256.41 ng/mg and the S-AP concentrations ranged from 0.11 to 23.31 ng/mg in the 120 segments. S-MA and S-AP were the most common analytes identified in hair; no R-MA or R-AP was found. The S-AP/S-MA ratios ranged from 0.03 to 0.32, indicating that the subjects primarily consumed S-MA rather than R-MA or AP. The S-AP/S-MA ratios in the long hair of all chronic MA abusers showed some variation, but there was an overall trend of gradual increase from the distal to the proximal end. This trend was independent of the drug concentrations. Therefore, we could conclude that the AP/MA ratios increased with the duration of MA abuse, and a higher AP/MA ratio suggested high MA dependence. There was no chiral conversion of MA or AP in the hair matrix. The segmental hair analysis showed that all subjects continuously used S-MA, and some users showed an increase in drug dose or the frequency of use.

scholarly journals Experimental Central Nervous System Aspergillosis Therapy: Efficacy, Drug Levels and Localization, Immunohistopathology, and Toxicity

2012 ◽  
Vol 56 (8) ◽  
pp. 4439-4449 ◽  
Author(s):  
Karl V. Clemons ◽  
Julie A. Schwartz ◽  
David A. Stevens
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Amphotericin B ◽  
Cell Activation ◽  
High Dose ◽  
Endothelial Cell Activation ◽  
Content Type ◽  
Drug Concentrations ◽  
Cyclophosphamide Treatment ◽  
Renal Tubular

ABSTRACTWe have shown previously that high-dose lipid amphotericin preparations are not more efficacious than lower doses in aspergillosis. We studied toxicity, drug concentrations and localization, and quantitative infection concurrently, using a 4-day model of central nervous system (CNS) aspergillosis to assess early events. Mice givenAspergillus fumigatusconidia intracerebrally, under a cyclophosphamide immunosuppressive regimen, were treated for 3 days (AmBisome at 3 or 10 mg/kg of body weight, Abelcet at 10 mg/kg, amphotericin B deoxycholate at 1 mg/kg, caspofungin at 5 mg/kg, or voriconazole at 40 mg/kg). Sampling 24 h after the last treatment showed that AmBisome at 3 but not at 10 mg/kg, as well as Abelcet, caspofungin, and voriconazole, reduced brain CFU. All regimens reduced renal infection. Minor renal tubular changes occurred with AmBisome or Abelcet therapy, whereas heart, lung, and brain showed no drug toxicity. Amphotericin B tissue and serum concentrations did not correlate with efficacy. Endothelial cell activation (ICAM-1 and P-selectin in cerebral capillaries) occurred during infection. Amphotericin B derived from AmBisome and Abelcet localized in activated endothelium and from Abelcet in intravascular monocytes. In 10-day studies dosing uninfected mice, minor renal tubular changes occurred after AmBisome or Abelcet at 1, 5, or 10 mg/kg with or without cyclophosphamide treatment; nephrosis occurred only with Abelcet in cyclophosphamide-treated mice. Hepatotoxicity occurred with AmBisome and Abelcet but was reduced in cyclophosphamide-treated mice. Marked CFU reduction by AmBisome at 3 mg/kg occurred in association with relatively more intense inflammation. Abelcet renal localization appears to be a precursor to late nephrotoxicity. Hepatotoxicity may contribute to high-dose Abelcet and AmBisome failures. Our novel observation of endothelial amphotericin localization during infection may contribute to amphotericin mechanism of efficacy.

Modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea pig lungs using methylprednisolone

2008 ◽  
Vol 295 (6) ◽  
pp. L998-L1006 ◽  
Author(s):  
Koki Kamiyama ◽  
Naoyuki Matsuda ◽  
Seiji Yamamoto ◽  
Ken-ichi Takano ◽  
Yasuo Takano ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Cell Apoptosis ◽  
Nuclear Translocation ◽  
Lavage Fluid ◽  
Dominant Negative ◽  
Receptor Expression ◽  
Immunofluorescent Staining ◽  
Terminal Deoxynucleotidyl Transferase ◽  
High Dose ◽  
Mobility Shift

The use of glucocorticoids for treatment of sepsis has waxed and waned during the past several decades, and recent randomized controlled trials have evoked a reassessment of this therapy. Most glucocorticoid actions are mediated by its specific intracellular receptors (GRs). Thus we initially evaluated whether sepsis and high-dose corticosteroid therapy can regulate guinea pig pulmonary expression of GRs: active receptor, GRα, and dominant negative receptor, GRβ. Sepsis induction by LPS injection (300 μg/kg ip) decreased mRNA and protein levels of GRα and increased protein expression of GRβ in lungs. High-dose methylprednisolone (40 mg/kg ip), administered simultaneously with LPS, markedly potentiated the decrease in GRα expression but slightly affected the increase in GRβ expression. Consequently, this led to a significant reduction in GRα nuclear translocation. Nevertheless, methylprednisolone treatment strongly eliminated LPS induction of NF-κB activity, as determined by NF-κB nuclear translocation and by gel mobility shift assays. Furthermore, the LPS-induced increase in inflammatory cells in bronchoalveolar lavage fluid was blunted by administration of the corticosteroid. On the other hand, immunofluorescent staining for cleaved caspase-3 showed a marked increase in this proapoptotic marker in lung sections, and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) represented an enhanced appearance of cell apoptosis in lungs and spleen when methylprednisolone was given together with LPS. Cell apoptosis is now considered to play a role in the pathogenesis of septic syndrome. We thus suggest that the action of glucocorticoids at high doses to accelerate sepsis-induced cell apoptosis may overwhelm their therapeutic advantages in septic shock.

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