Sex-dependent metabolism of ketamine and (2R,6R)-hydroxynorketamine in mice and humans

Background: Ketamine is rapidly metabolized to norketamine and hydroxynorketamine (HNK) metabolites. In female mice, when compared to males, higher levels of ( 2R,6R;2S,6S)-HNK have been observed following ketamine treatment, and higher levels of ( 2R,6R)-HNK following the direct administration of ( 2R,6R)-HNK. Aim: The objective of this study was to evaluate the impact of sex in humans and mice, and gonadal hormones in mice on the metabolism of ketamine to form norketamine and HNKs and in the metabolism/elimination of ( 2R,6R)-HNK. Methods: In CD-1 mice, we utilized gonadectomy to evaluate the role of circulating gonadal hormones in mediating sex-dependent differences in ketamine and ( 2R,6R)-HNK metabolism. In humans (34 with treatment-resistant depression and 23 healthy controls) receiving an antidepressant dose of ketamine (0.5 mg/kg i.v. infusion over 40 min), we evaluated plasma levels of ketamine, norketamine, and HNKs. Results: In humans, plasma levels of ketamine and norketamine were higher in males than females, while ( 2R,6R;2S,6S)-HNK levels were not different. Following ketamine administration to mice (10 mg/kg i.p.), Cmax and total plasma concentrations of ketamine and norketamine were higher, and those of ( 2R,6R;2S,6S)-HNK were lower, in intact males compared to females. Direct ( 2R,6R)-HNK administration (10 mg/kg i.p.) resulted in higher levels of ( 2R,6R)-HNK in female mice. Ovariectomy did not alter ketamine metabolism in female mice, whereas orchidectomy recapitulated female pharmacokinetic differences in male mice, which was reversed with testosterone replacement. Conclusion: Sex is an important biological variable that influences the metabolism of ketamine and the HNKs, which may contribute to sex differences in therapeutic antidepressant efficacy or side effects.

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Antioxidants Promote Intestinal Tumor Progression in Mice

Antioxidants ◽

10.3390/antiox10020241 ◽

2021 ◽

Vol 10 (2) ◽

pp. 241

Author(s):

Zhiyuan V. Zou ◽

Kristell Le Gal ◽

Ahmed E. El Zowalaty ◽

Lara E. Pehlivanoglu ◽

Viktor Garellick ◽

...

Keyword(s):

Oxidative Stress ◽

Colorectal Cancer ◽

Tumor Progression ◽

Human Subjects ◽

Plasma Concentrations ◽

Intestinal Tumor ◽

Adenomatous Polyposis ◽

Intestinal Tumors ◽

The Impact

Dietary antioxidants and supplements are widely used to protect against cancer, even though it is now clear that antioxidants can promote tumor progression by helping cancer cells to overcome barriers of oxidative stress. Although recent studies have, in great detail, explored the role of antioxidants in lung and skin tumors driven by RAS and RAF mutations, little is known about the impact of antioxidant supplementation on other cancers, including Wnt-driven tumors originating from the gut. Here, we show that supplementation with the antioxidants N-acetylcysteine (NAC) and vitamin E promotes intestinal tumor progression in the ApcMin mouse model for familial adenomatous polyposis, a hereditary form of colorectal cancer, driven by Wnt signaling. Both antioxidants increased tumor size in early neoplasias and tumor grades in more advanced lesions without any impact on tumor initiation. Importantly, NAC treatment accelerated tumor progression at plasma concentrations comparable to those obtained in human subjects after prescription doses of the drug. These results demonstrate that antioxidants play an important role in the progression of intestinal tumors, which may have implications for patients with or predisposed to colorectal cancer.

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Role of the Pharmacist in Managing Treatment-Resistant Depression: A Focus on Ketamine

Pharmacy ◽

10.3390/pharmacy9030118 ◽

2021 ◽

Vol 9 (3) ◽

pp. 118

Author(s):

Linda Xing Yu Liu ◽

Marina Golts ◽

Virginia Fernandes

Keyword(s):

Current Practice ◽

Quality Care ◽

Treatment Options ◽

Critical Role ◽

Transitions Of Care ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Resistant Depression ◽

Multiple Treatments ◽

The Impact

The impact of depression is well described in the literature, and it is most prominent in patients who have trialed multiple treatments. Treatment-resistant depression (TRD) is particularly debilitating, and it is associated with significant morbidity and mortality. Despite this, there seems to be therapeutic inertia in adopting novel therapies in current practice. Ketamine is an N-methyl-D-aspartate receptor antagonist and anesthetic agent which has recently been shown to be effective in the management of TRD when administered intravenously or intranasally. The treatments, however, are not easily accessible due to restrictions in prescribing and dispensing, high costs, and the slow uptake of evidence-based practice involving ketamine within the Canadian healthcare system. Given the limited treatment options for TRD, novel approaches should be considered and adopted into practice, and facilitated by a multi-disciplinary approach. Pharmacists play a critical role in ensuring access to quality care. This includes dissemination of evidence supporting pharmacological treatments and facilitating translation into current practice. Pharmacists are uniquely positioned to collaborate with prescribers and assess novel treatment options, such as ketamine, address modifiable barriers to treatment, and triage access to medications during transitions of care. Extending the reach of these novel psychiatric treatments in both tertiary and primary care settings creates an emerging role for pharmacists in the collaborative effort to better manage treatment-resistant depression.

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P.0671 The role of intranasal ketamine in treatment-resistant depression

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2021.10.633 ◽

2021 ◽

Vol 53 ◽

pp. S492

Author(s):

M. Costa ◽

M. Fraga ◽

A. Moutinho ◽

P. Cintra

Keyword(s):

Treatment Resistant Depression ◽

Treatment Resistant ◽

Resistant Depression

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Oral esketamine for treatment-resistant depression: rationale and design of a randomized controlled trial

BMC Psychiatry ◽

10.1186/s12888-019-2359-1 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 3

Author(s):

Sanne Y. Smith-Apeldoorn ◽

Jolien K. E. Veraart ◽

Jeanine Kamphuis ◽

Antoinette D. I. van Asselt ◽

Daan J. Touw ◽

...

Keyword(s):

Controlled Trial ◽

Treatment Strategies ◽

Repeated Administration ◽

Additional Treatment ◽

Racemic Mixture ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Routes Of Administration ◽

Antidepressant Efficacy ◽

Resistant Depression

Abstract Background There is an urgent need to develop additional treatment strategies for patients with treatment-resistant depression (TRD). The rapid but short-lived antidepressant effects of intravenous (IV) ketamine as a racemic mixture have been shown repeatedly in this population, but there is still a paucity of data on the efficacy and safety of (a) different routes of administration, and (b) ketamine’s enantiomers esketamine and arketamine. Given practical advantages of oral over IV administration and pharmacodynamic arguments for better antidepressant efficacy of esketamine over arketamine, we designed a study to investigate repeated administration of oral esketamine in patients with TRD. Methods This study features a triple-blind randomized placebo-controlled trial (RCT) comparing daily oral esketamine versus placebo as add-on to regular antidepressant medications for a period of 6 weeks, succeeded by a follow-up of 4 weeks. The methods support examination of the efficacy, safety, tolerability, mechanisms of action, and economic impact of oral esketamine in patients with TRD. Discussion This is the first RCT investigating repeated oral esketamine administration in patients with TRD. If shown to be effective and tolerated, oral esketamine administration poses important advantages over IV administration. Trial registration Dutch Trial Register, NTR6161. Registered 21 October 2016.

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Managing Esketamine Treatment Frequency Toward Successful Outcomes: Analysis of Phase 3 Data

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyaa027 ◽

2020 ◽

Vol 23 (7) ◽

pp. 426-433 ◽

Cited By ~ 2

Author(s):

Michel Nijs ◽

Ewa Wajs ◽

Leah Aluisio ◽

Ibrahim Turkoz ◽

Ella Daly ◽

...

Keyword(s):

Nasal Spray ◽

Rating Scale ◽

Maintenance Phase ◽

Induction Phase ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Open Label ◽

Treatment Frequency ◽

Resistant Depression ◽

The Impact

Abstract Background Esketamine nasal spray was recently approved for treatment-resistant depression. The current analysis evaluated the impact of symptom-based treatment frequency changes during esketamine treatment on clinical outcomes. Methods This is a post-hoc analysis of an open-label, long-term (up to 1 year) study of esketamine in patients with treatment-resistant depression (SUSTAIN 2). During a 4-week induction phase, 778 patients self-administered esketamine twice weekly plus a new oral antidepressant daily. In responders (≥50% reduction in Montgomery-Åsberg Depression Rating Scale total score from baseline), esketamine treatment frequency was thereafter decreased during an optimization/maintenance phase to weekly for 4 weeks and then adjusted to the lowest frequency (weekly or every other week) that maintained remission (Montgomery-Åsberg Depression Rating Scale ≤ 12) based on a study-defined algorithm. The relationship between treatment frequency and symptom response, based on clinically meaningful change in Clinical Global Impression–Severity score, was subsequently evaluated 4 weeks after treatment frequency adjustments in the optimization/maintenance phase. Results Among 580 responders treated with weekly esketamine for the first 4 weeks in the optimization/maintenance phase (per protocol), 26% continued to improve, 50% maintained clinical benefit, and 24% worsened. Thereafter, when treatment frequency could be reduced from weekly to every other week, 19% further improved, 49% maintained benefit, and 32% worsened. For patients no longer in remission after treatment frequency reduction, an increase (every other week to weekly) resulted in 47% improved, 43% remained unchanged, and 10% worsened. Conclusions These findings support individualization of esketamine nasal spray treatment frequency to optimize treatment response in real-world clinical practice. Trial Registration ClinicalTrials.gov identifier: NCT02497287

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EFFECTS OF PINEALECTOMY ON THE SECRETION OF LUTEINIZING HORMONE, TESTOSTERONE AND PROLACTIN IN RAMS EXPOSED TO VARIOUS LIGHTING RÉGIMES

Journal of Endocrinology ◽

10.1677/joe.0.0800397 ◽

1979 ◽

Vol 80 (3) ◽

pp. 397-405 ◽

Cited By ~ 29

Author(s):

G. K. BARRELL ◽

K. R. LAPWOOD

Keyword(s):

Luteinizing Hormone ◽

Pineal Gland ◽

Plasma Levels ◽

Seasonal Changes ◽

Peak Plasma ◽

Plasma Concentrations

Two experiments were carried out to study the effects of controlled lighting régimes on plasma levels of LH, testosterone and prolactin in Romney rams. In the second experiment the rams were either pinealectomized or sham-operated so that the role of the pineal gland in mediating seasonal changes in reproduction could be examined. Levels of testosterone and prolactin were considerably influenced by the lighting schedule. Peak plasma concentrations of testosterone were associated with periods during which the daily photoperiod decreased, whereas plasma levels of prolactin showed a pattern of changes approximately in phase with the lighting cycles. Mean plasma concentrations of LH were low in all groups of rams, which made the detection of significant effects of any treatment very unlikely. Pinealectomy reduced the effects of changes in the daily photoperiod on the patterns of secretion of testosterone and prolactin. These findings establish the pineal gland as an organ which influences the endocrine responses of rams to photoperiodic stimuli and it is concluded that the pineal gland is probably important as a mediator of seasonal reproductive changes in these animals.

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Retrospective Study of Trough Imatinib Plasma Levels Conducted as Part of the Follow-up of Patients with Chronic Myeloid Leukemia in a Canadian Cohort

Blood ◽

10.1182/blood.v112.11.4258.4258 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4258-4258

Author(s):

Rahima Jamal ◽

Danielle Desmarais ◽

John Chapdelaine ◽

Yvan Côté ◽

Lambert Busque

Keyword(s):

Chronic Myeloid Leukemia ◽

Plasma Levels ◽

Myeloid Leukemia ◽

Plasma Concentrations ◽

The Body ◽

Inadequate Response ◽

Molecular Responses ◽

The Impact ◽

Trough Levels

Abstract While imatinib biodisponibility is excellent, trough imatinib plasma levels associated with standard dose imatinib are variable and cannot be predicted by the age, the body surface area or the weight of the patient. Imatinib trough levels have recently been associated with both cytogenetic and molecular responses, making imatinib pharmacokinetics a possible target in optimisation of the treatment of patients with chronic myeloid leukemia. We retrospectively analysed trough imatinib plasma levels prescribed as part of the longitudinal follow-up of a cohort of patients with chronic myeloid leukemia in Canada. Indications for testing were inadequate response, important side effects or suspicion of non compliance. The objectives of the study were to evaluate the variability of trough imatinib plasma levels in our cohort and determine the impact a first result had on the subsequent plasma level in patients with more than one imatinib plasma determination. Analyses of trough plasma levels in 278 patients were conducted in a central canadian laboratory from April 2007 to April 2008. Trough imatinib plasma levels were measured using liquid chromatography and tandem mass spectrometry (LC/MS/MS) with deuterated imatinib as the internal standard. Distribution of trough imatinib plasma levels according to the established IRIS quartiles (Q1–Q4; BLOOD. 2008, vol 11, p4022)) showed an important variability, with plasma levels distributed between less than 100 ng/ml and more than 4500 ng/ml. Sixty-two (22.3%) patients in our cohort had plasma levels below 647 ng/ml (Q1), 101(36.3%) patients had levels between 647–1170 ng/ml (Q2–Q3) and 115 (41.3%) patients had trough levels above 1170 ng/ml (Q4). There were 31 patients (11.2%) with levels above 2000 ng/ml, all of whom were included in the Q4. Thirty seven patients in our cohort had more than one analysis of trough imatinib plasma levels done during the one year follow-up for a total of 82 analyses. Sub-group analysis of trough imatinib plasma levels was conducted in the 13 patients in the Q1 and the six patients in the Q4 who had 2 analyses done. Mean trough imatinib plasma levels went from 401ng/ml to 665 ng/ml in the Q1 patients and from 2845 ng/ml to 1065 ng/ml in the Q4 patients. These results confirm the feasibility of imatinib plasma levels testing in the community and the important variability of trough imatinib plasma concentrations in individual patients, as described by other groups. A significant portion of patients in our cohort had trough levels below 647 ng/ml, which has been associated with less favourable cytogenetic and molecular responses in studies. These results also suggest that physicians act on the information procured by the determination of imatinib plasma levels as second level determination was improved for patients initially in Q1 or Q4. Further follow up analyses are needed to document if optimisation of dosing leads to better response or improvement in tolerability of the drug.

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Hypoxia induced HIF1a-mediated O-GalNAc glycosylation of cytosolic O-GlcNAcylated proteins to regulate signaling pathways in pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15739 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15739-e15739

Author(s):

Gerrit Wolters-Eisfeld ◽

Baris Mercanoglu ◽

Alina Strohmaier ◽

Cenap Guengoer ◽

Jakob R. Izbicki ◽

...

Keyword(s):

Pancreatic Cancer ◽

Early Stage ◽

Tumor Development ◽

Hek293 Cells ◽

Treatment Resistant ◽

Tn Antigen ◽

Cell Energy ◽

Hif Pathway ◽

The Impact

e15739 Background: Hypoxia induced reprogramming of cell energy metabolism and changes in glycosylation are hallmarks of cancer promoting the induction of an invasive and treatment-resistant phenotype, triggering metastases at an early stage of tumor development. We examined the impact of hypoxia on O-GalNAc glycosylation in human HEK293, PDAC cell lines and clinical specimens. Methods: We profiled the expression of 88 glycosylation related genes by qPCR in HEK293 cells subjected to hypoxia either induced by 1% O2 or 200 mm CoCl2 identifying key O-GalNAc glycosyltransferases downregulated. Functional assays and glycoprotein analysis displayed a pronounced rate of O-GalNAc modified cytosolic proteins derived from hypoxia treated cells and PDAC specimens. Glycosidase assays could validate specificity of detection method used. Aberrant glycotype could be induced by HIF pathway activator ML 228 and inhibited using Echinomycin. PTK and STK analysis of cell lysates displayed correlation between phosphorylation and O-glycosylation in hypoxic samples. Results: Mechanistically we could show, that hypoxia induced decreased levels of C1GALT1C1 results in reduced T-Synthase activity with subsequent expression of truncated O-glycans (Tn antigen). Differential O-GalNAc glycosylation is inducible using HIF pathway activator ML228 under normoxia and the effect is reversed using 5 µM Echinomycin under hypoxia underscoring the role of HIF1a regulated transcription. Interestingly, the pattern of Tn antigen modified proteins derived from hypoxic samples differs significantly from engineered COSMC deficient cells, displaying O-GalNAc moieties in addition to O-GlcNAc in cytosolic protein fractions. Conclusions: Our findings point to a novel crosstalk of O-GalNAc and O-GlcNAcylation under hypoxia extending the knowledge base of differential O-GalNAc glycosylation in pancreatic cancer.

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