Possible Mechanisms for the Therapeutic Window in the Antidepressant Action of Tryptophan

2015 ◽  
pp. 147-152
Author(s):  
Simon N. Young ◽  
Candace J. Gibson ◽  
Serge Gauthier
Keyword(s):  
Therapeutic Window ◽  
Antidepressant Action

Highly Potent rhenium(I) Tricarbonyl Complexes with Dual Anticancer and Anti-Angiogenic Activity Against Colorectal Carcinoma

2020 ◽  
Author(s):  
Joachim Delasoie ◽  
Aleksandar Pavic ◽  
Noémie Voutier ◽  
Sandra Vojnovic ◽  
Aurélien Crochet ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Anticancer Drugs ◽  
Xenograft Model ◽  
Therapeutic Window ◽  
Low Doses ◽  
Sunitinib Malate ◽  
Angiogenic Activity ◽  
Antimetastatic Activity ◽  
Clinical Drugs

Synthesized and characterized a series of rhenium(I) trycarbonyl-based complexes with increased lipophilicity. Two of these novel compounds were discovered to possess remarkable anticancer, anti-angiogenic and antimetastatic activity <i>in vivo</i> (zebrafish-human CRC xenograft model), being effective at very low doses (1-3 µM). At doses as high as 250 µM the complexes did not provoke toxicity issues encountered in clinical anticancer drugs (cardio-, hepato-, and myelotoxicity). The two compounds exceed the antiproliferative and anti-angiogenic potency of clinical drugs cisplatin and sunitinib-malate, and display a large therapeutic window.

Targeted Therapies for Autosomal Dominant Polycystic Kidney Disease

2019 ◽  
Vol 26 (17) ◽  
pp. 3081-3102 ◽  
Author(s):  
Cherie Stayner ◽  
Darby G. Brooke ◽  
Michael Bates ◽  
Michael R. Eccles
Keyword(s):  
Clinical Trial ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Targeted Therapies ◽  
Autosomal Dominant ◽  
Current Treatment ◽  
Therapeutic Window ◽  
Polycystic Kidney ◽  
Ion Release ◽  
Autosomal Dominant Polycystic Kidney

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening genetic disease in humans, affecting approximately 1 in 500 people. ADPKD is characterized by cyst growth in the kidney leading to progressive parenchymal damage and is the underlying pathology in approximately 10% of patients requiring hemodialysis or transplantation for end-stage kidney disease. The two proteins that are mutated in ADPKD, polycystin-1 and polycystin-2, form a complex located on the primary cilium and the plasma membrane to facilitate calcium ion release in the cell. There is currently no Food and Drug Administration (FDA)-approved therapy to cure or slow the progression of the disease. Rodent ADPKD models do not completely mimic the human disease, and therefore preclinical results have not always successfully translated to the clinic. Moreover, the toxicity of many of these potential therapies has led to patient withdrawals from clinical trials. Results: Here, we review compounds in clinical trial for treating ADPKD, and we examine the feasibility of using a kidney-targeted approach, with potential for broadening the therapeutic window, decreasing treatment-associated toxicity and increasing the efficacy of agents that have demonstrated activity in animal models. We make recommendations for integrating kidney- targeted therapies with current treatment regimes, to achieve a combined approach to treating ADPKD. Conclusion: Many compounds are currently in clinical trial for ADPKD yet, to date, none are FDA-approved for treating this disease. Patients could benefit from efficacious pharmacotherapy, especially if it can be kidney-targeted, and intensive efforts continue to be focused on this goal.

scholarly journals Urothelial toxicity of esketamine in the treatment of depression

2020 ◽  
Vol 237 (11) ◽  
pp. 3295-3302
Author(s):  
Hannelore Findeis ◽  
Cathrin Sauer ◽  
Anthony Cleare ◽  
Michael Bauer ◽  
Philipp Ritter
Keyword(s):  
Laboratory Data ◽  
Rapid Onset ◽  
Treatment Schedule ◽  
Treatment Of Depression ◽  
Icd 10 ◽  
Repeated Doses ◽  
Free Haemoglobin ◽  
Leukocyte Concentration ◽  
Depression Ratings ◽  
Antidepressant Action

Abstract Rationale Ketamine is the first widely used substance with rapid-onset antidepressant action. However, there are uncertainties regarding its potential urothelial toxicity, particularly after repeated application. In the context of rising recreational ketamine use, severe side effects affecting the human urinary tract have been reported. It is assumed that ketamine interacts with bladder urothelial cells and induces apoptosis. Objectives This study aimed to assess whether single or repeated doses of esketamine used in an antidepressant indication are associated with urinary toxicity. Methods We included male and female inpatients with a current episode of depression and a diagnosis of recurrent depressive disorder, bipolar disorder or schizoaffective disorder according to ICD-10 criteria (n = 25). The esketamine treatment schedule involved a maximum of 3× weekly dosing at 0.25–0.5 mg/kg i.v. or s.c. The primary outcome was the change in urine toxicity markers (leukocytes, erythrocytes, protein and free haemoglobin). Description of demographic, clinical and laboratory data was conducted using means, standard deviations, frequencies and percentages. Changes in urinary toxicity markers over time were evaluated using linear mixed models with gender as a covariate. Results The participants received an average of 11.4 (SD 8) esketamine treatments, and an average number of 11.2 (SD 8) urine samples were analysed over the course of treatment. Neither urinary leukocyte concentration (F(20; 3.0) = 3.1; p = 0.2) nor erythrocyte concentration (F(20;2.2) = 4.1; p = 0.2) showed a significant trend towards increase during the course of esketamine treatment. Similarly, free haemoglobin and protein concentrations, which were analysed descriptively, did not display a rise during treatment. There was a significant improvement in depression ratings after esketamine treatment (p < 0.001). Conclusions This study is, to the best of our knowledge, the first to focus on urothelial toxicity of esketamine used in antidepressant indication and dose. The results indicate that the use of single or repeated doses of esketamine is unlikely to cause urothelial toxicity. The results are in need of confirmation as sample size was small.

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