Trazodone is approved for the treatment of major depressive disorders, marketed as immediate release (IR), prolonged release, and once a day (OAD) formulation. The different formulations allow different administration schedules and may be useful to facilitate patients’ compliance to the antidepressant treatment. A previously verified physiologically‐based pharmacokinetic model based on in vitro and in vivo information on trazodone pharmacokinetics was applied, aiming at predicting brain receptor occupancy (RO) after single and repeated dosing of the IR formulation and repeated dosing of the OAD formulation in healthy subjects. Receptors included in the simulations were selected using static calculations of RO based on the maximum unbound brain concentration (Cmax,brain,u) of trazodone for each formulation and dosing scheme, resulting in 16 receptors being simulated. Seven receptors were simulated for the IR low dose formulation (30 mg), with similar tonset and duration of coverage (range: 0.09–0.25 h and 2.1–>24 h, respectively) as well as RO (range: 0.64–0.92) predicted between day 1 and day 7 of dosing. The 16 receptors evaluated for the OAD formulation (300 mg) showed high RO (range: 0.97–0.84 for the receptors also covered by the IR formulation and 0.73–0.48 for the remaining) correlating with affinity and similar duration of time above the target threshold to the IR formulation (range: 2–>24 h). The dose‐dependent receptor coverage supports the multimodal activity of trazodone, which may further contribute to its fast antidepressant action and effectiveness in controlling different symptoms in depressed patients. Study Highlights
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
The antidepressant efficacy of trazodone has been shown to be significantly correlated to its steady‐state plasma levels, and previous work has shown some understanding of trazodone range of affinity for different receptors, at different doses, but without considering the different available formulations. Trazodone is commonly available as: immediate release (IR), prolonged release (PR), and once a day (OAD) tablets. The IR formulation has a rapid onset and short duration of action, whereas the PR formulation is characterized by an absorption boost as soon as it is administered and has a comparatively delayed maximum concentration (Cmax). Conversely, the OAD formulation provides a controlled release of trazodone over 24 h without the early high peak plasma concentration seen with the IR and PR formulations.
WHAT QUESTION DID THIS STUDY ADDRESS?
This work aims to identify the brain receptors reaching a threshold occupancy of 50% through static predictions and determine the occupancy versus time profile for those of interest following administration of short‐ and long‐acting trazodone formulations.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
Brain receptor occupancy (RO) for key targets were predicted based on free drug concentrations, allowing for a physiologically relevant assessment of the different pathways affected by each formulation and dose.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
The presented physiologically‐based pharmacokinetic approach to assess RO can be used to guide formulation selection and dosing in clinical studies. 相似文献
The aim of this study was to investigate the influence of systemic chemotherapy on the skeletal growth of young osteosarcoma patients as a treatment-related late adverse effect. We reviewed the height data of 20 osteosarcoma patients (13 males and 7 females) aged ≤18 years. The average (±SD) age at diagnosis was 14.5 (±3.3) years. The average follow-up interval was 89.6 months. After wide resection of the affected bones, reconstruction with tumor prostheses and auto-bone grafting was carried out in 11 and 9 cases, respectively. Pearson’s correlation coefficient was calculated to evaluate the association between actual and predicted (using Paley’s multiplier method) heights. Z-scores were used to compare the initial and final heights with the Japanese national growth curve. Actual and predicted heights were correlated according to Pearson’s correlation coefficient (R = 0.503). Z-analysis showed that statistical significance (p = 0.04) was noted for the height data Z-scores of patients between ≤10 years and >10 years at the final follow-up. Systemic chemotherapy did not reduce skeletal growth in young osteosarcoma patients as a late adverse effect based on two different evaluation methods. However, patients aged ≤10 years at diagnosis may develop a short stature after systemic chemotherapy. 相似文献
Objective Peripherally inserted central catheters (PICCs) are widely used in patients with hematologic malignancies. However, the risks of PICC-related complications during chemotherapy for acute myeloid leukemia (AML) are not fully understood. Methods We conducted a retrospective review of 128 adult patients with AML who received induction therapy by way of PICC insertion between 2012 and 2019. Results The median duration of PICC insertion was 30 days. The incidence rate of catheter-related bloodstream infection (CRBSI) was 2.4% at 30 days, and women were more likely to suffer from CRBSI than men. Local reactions at the insertion site were observed in 56 patients; however, these events did not predict CRBSI. The incidence rates of catheter-related thrombosis (CRT) were 1.6% at 30 days. Obesity put patients at an increased risk for CRT. Unexpected PICC removal occurred in 59 patients, and women were at a higher risk of catheter removal than men. Conclusion Low PICC-related complication rates, possibly associated with high rates of catheter removal, were observed during intensive chemotherapy for AML. Women and obese patients require careful monitoring of their PICC. Procedures to achieve appropriate PICC removal without increasing the complication rate need to be considered. 相似文献
Spinal cord arteriovenous malformation (AVM) associated with spinal aneurysm is not particularly rare, but cases presenting with hematomyelia are relatively rare compared to those with subarachnoid hemorrhage (SAH). We report a rare case of successfully treated spinal AVM associated with ruptured aneurysm presenting with hematomyelia.
CASE DESCRIPTION
A 52-year-old male was admitted to our hospital with sudden onset of tetraplegia, respiratory disturbance, and superficial sensory disturbance. Computed tomography revealed hematomyelia at the level of C3–4. Gadolinium-enhanced magnetic resonance imaging showed small, enhanced lesions. Angiography revealed an intradural perimedullary arteriovenous malformation associated with two aneurysms on the feeding arteries. Administration of high-dose methylprednisolone gradually ameliorated his symptoms. Direct surgical obliteration was performed on the 30th day after the onset. The bilateral C3 cervical radicular arteries and the nidus were coagulated. Angiography performed after surgery showed neither the aneurysms nor the nidus. He was discharged with only mild weakness in the left upper extremity and mild left hypesthesia 3 months after surgery, and was fully independent.
CONCLUSION
We report a case of hematomyelia caused by ruptured aneurysm associated with spinal arteriovenous malformation that was successfully treated with surgical obliteration. 相似文献
A 5-year review of nosocomial infections, bacteraemia and wound colonization in patients admitted to a burn intensive care unit from June 2001 to May 2006 was carried out. All patients required intubation at some point, and ICU support. Data on bacterial and fungal isolates were entered prospectively into a hospital-wide computerized database. Nosocomial infections (NIs) were defined using standard CDC criteria. Seventy-six patients were admitted during the study period, with 57 qualifying for analysis. Forty-two patients (74%) developed 137 NIs, with 240 NIs/100 admissions. The most common NI was pneumonia (43%), followed by burn wound infection (34%), primary bloodstream infection (20%) and urinary tract infection (3%). The device specific rate of pneumonia was 143 infections per 1000 ventilator days. There were 113 episodes of bacteraemia and 173 episodes of wound colonization without infection. The most common organisms causing nosocomial infections were Acinetobacter sp. (n = 33), followed by methicillin resistant Staphylococcus aureus (MRSA) (n = 24) and Pseudomonas aeruginosa (n = 22). A. baumannii isolates were highly multiresistant, with 82 distinct strains isolated from 47 patients (82% of patients). Data from this and other studies supports the hypothesis that A. baumannii is more common in tropical, warm climes necessitating vigorous infection control measures to optimise patient outcome. 相似文献
Backgrounds Pelvic autonomic nerve preservation (PANP) with lateral lymph node dissection (LLND) has been introduced in rectal cancer
surgery in Japan; however, its indication has not been standardized yet.
Materials and methods Forty-four patients with advanced lower rectal cancer were randomized to either the standard treatment group (control group)
or the intraoperative radiotherapy (IORT) group. All patients underwent potentially curative resection of the rectum with
total mesorectal excision. The control group underwent bilateral LLND and limited PANP. The IORT group underwent bilateral
LLND, complete PANP, and IORT. Patients allocated to the IORT group received IORT to the bilateral preserved pelvic nerve
plexuses. Patients’ clinicopathologic parameters, postoperative complications, voiding function, and prognosis were compared
between the two groups.
Results Among 44 patients enrolled, three patients were excluded from the analysis, resulting in 19 patients in the IORT group and
22 patients in the control group. Patients’ demographic and pathological parameters and postoperative complications were well
balanced between the two groups. Oncological outcomes including overall and disease-free survival were also similar. Local
recurrence was observed in one patient in each group. Among the 34 patients not complicated with intrapelvic abscess, the
mean duration of urinary catheter indwelling was 8 days in the IORT group and 13 days in the control group (p = 0.055). In the long term, medication for urination was necessitated in four patients in the control group, whereas in none
in the IORT group (p = 0.059).
Discussions Oncological outcomes in the IORT group are equal to those in the control group, and voiding functions in the IORT group are
superior to those in the control group. These results suggest that IORT may be useful to expand the indication of complete
PANP with LLND for advanced lower rectal cancer. 相似文献
This study was designed to determine the optimum treatment for a superficial esophageal cancer involving the mucosal or submucosal
layer of the esophagus. The subjects were 150 patients with a superficial esophageal cancer who underwent endoscopic mucosal
resection (EMR) or esophagectomy in Kurume University Hospital from 1981 to 1997. The mortality and morbidity rates, survival
rate, and recurrence rate were retrospectively compared for (1) 35 patients who underwent EMR and 37 patients who underwent
esophagectomy for a mucosal esophageal cancer and (2) 45 patients who underwent extended radical esophagectomy and 33 patients
who underwent less radical esophagectomy for a submucosal esophageal cancer. Among the 72 patients with a mucosal cancer,
lymph node metastasis/recurrence was observed in only one (1%); whereas of 78 patients with a submucosal cancer it was observed
in 30 (38%). Among patients with a mucosal cancer the mortality and morbidity rates after EMR were lower than for those after
esophagectomy. The survival rate after EMR was the same as that after esophagectomy. No recurrence was observed after either
treatment modality. Among the patients with a submucosal cancer, the survival rate was higher and the recurrence rate lower
after extended radical esophagectomy; than after less radical esophagectomy; the mortality and morbidity rates after extended
radical esophagectomy were the same as those after less radical esophagectomy. Multivariate analysis demonstrated that the
treatment modality (EMR versus esophagectomy) did not influence the survival of patients with a mucosal esophageal cancer,
whereas it strongly influenced the survival of patients with a submucosal esophageal cancer. We concluded that EMR was the
mainstay of treatment for a mucosal esophageal cancer, and extended radical esophagectomy was the mainstay of treatment for
a submucosal esophageal cancer. 相似文献
The epidural stimulation test can help detect if a catheter is correctly positioned in the epidural space. Previous studies showed that a current of up to 16 mA was required to elicit a motor response, but few peripheral nerve stimulators can produce a current this high. Manipulating pulse width can produce a positive response at a lower current. To clarify the effects of pulse width on the epidural stimulation test, we performed a single-blinded study in a porcine model to estimate the equivalent current needed at varying pulse widths.
Methods
After obtaining local ethics approval, an 18G insulated Tuohy needle was advanced into the epidural space at the lower lumbar spinal level, and a 20G stimulating epidural catheter was advanced 30 cm cephalad. A gradually increasing electrical current was applied, and a motor response was elicited at pulse widths of 0.1, 0.2, 0.3, 0.5, and 1 msec. This was followed by a 1-2 cm catheter withdrawal, and the process was repeated for a total of 15 locations per pig.
Results
Recorded threshold currents ranged from 0.36-9.5 mA at a pulse width of 0.2 msec. Our results show a linear relationship between threshold current and pulse width.
Conclusions
In situations where different pulse widths are needed, the nomograms presented here may be useful to estimate the equivalent threshold current which is required to elicit a motor response according to previously published criteria for epidural stimulation tests. 相似文献