Population Pharmacokinetics and Pharmacodynamics of the Therapeutic and Adverse Effects of Ketamine in Patients With Treatment-Refractory Depression

We aimed to develop population pharmacokinetic/pharmacodynamic (PK/PD) models that can effectively describe ketamine and norketamine PK/PD relationships for Montgomery–Åsberg Depression Rating Scale (MADRS) scores, blood pressure (BP), and heart rate (HR) following i.v., s.c., and i.m. ketamine administration in patients with treatment-refractory depression. Ketamine PK/PD data were collected from 21 treatment-refractory depressed participants who received ketamine (dose titration 0.1–0.5 mg/kg as single doses) by i.v., s.c., or i.m. administration. Model development used nonlinear mixed effect modeling. Ketamine and norketamine PK were best described using two-compartment models with first-order absorption after s.c. and i.m. administration. Estimated ketamine bioavailability after i.m. and s.c. was ~ 64% with indistinguishable first-order absorption rate constants. Allometric scaling of body weight on all clearance and volumes of distribution improved the model fit. The delay in the concentration-response relationship for MADRS scores was best described using a turnover model (turnover time ~ 42 hours), whereas for the BP and HR rates this was an immediate effect model. For all PD effects, ketamine alone was superior to models with norketamine concentration linked to an effect. No covariates were identified for PD effects. The estimated half-maximal effective concentration from the MADRS score, BP, and HR were 0.44, 468, and 7,580 ng/mL, respectively. The integrated population models were able to effectively describe the PK/PD relationships for MADRS scores, BP, and HR after i.v., s.c., and i.m. ketamine administration. These findings allow for a deeper understanding of the complex relationships between route of ketamine administration and clinical response and safety

Can variability in the effect of opioids on refractory breathlessness be explained by genetic factors?

© 2015, BMJ Publishing Group. All rights reserved. Objectives: Opioids modulate the perception of breathlessness with a considerable variation in response, with poor correlation between the required opioid dose and symptom severity. The objective of this hypothesis-generating, secondary analysis was to identify candidate single nucleotide polymorphisms (SNP) from those associated with opioid receptors, signalling or pain modulation to identify any related to intensity of breathlessness while on opioids. This can help to inform prospective studies and potentially lead to better tailoring of opioid therapy for refractory breathlessness. Setting: 17 hospice/palliative care services (tertiary services) in 11 European countries. Participants: 2294 people over 18 years of age on regular opioids for pain related to cancer or its treatment. Primary outcome measures: The relationship between morphine dose, breathlessness intensity (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; EORTCQLQC30 question 8) and 112 candidate SNPs from 25 genes (n=588). Secondary outcome measures: The same measures for people on oxycodone (n=402) or fentanyl (n=429). Results: SNPs not in Hardy-Weinberg equilibrium or with allele frequencies (<5%) were removed. Univariate associations between each SNP and breathlessness intensity were determined with Benjamini-Hochberg false discovery rate set at 20%. Multivariable ordinal logistic regression, clustering over country and adjusting for available confounders, was conducted with remaining SNPs. For univariate morphine associations, 1 variant on the 5-hydroxytryptamine type 3B (HTR3B) gene, and 4 on the β-2-arrestin gene (ARRB2) were associated with more intense breathlessness. 1 SNP remained significant in the multivariable model: people with rs7103572 SNP (HTR3B gene; present in 8.4% of the population) were three times more likely to have more intense breathlessness (OR 2.86; 95% CIs 1.46 to 5.62; p=0.002). No associations were seen with fentanyl nor with oxycodone. Conclusions: This large, exploratory study identified 1 biologically plausible SNP that warrants further study in the response of breathlessness to morphine therapy

Evaluation of the activity of CYP2C19 in Gujrati and Marwadi subjects living in Mumbai (Bombay)

BACKGROUND: Inherited differences in the metabolism and disposition of drugs, and genetic polymorphisms in the targets of drug therapy (e.g., receptors), can greatly influence efficacy and toxicity of medications. Marked interethnic differences in CYP2C19 (a member of the cytochrome P-450 enzyme superfamily catalyzing phase I drug metabolism) which affects the metabolism of a number of clinically important drugs have been documented. The present study evaluated the activity of CYP2C19 in normal, healthy Gujrati and Marwadi subjects by phenotyping (a western Indian population). METHODS: All subjects received 20 mg of omeprazole, which was followed by blood collection at 3 hrs to estimate the metabolic ratio of omeprazole to 5-hydroxyomeprazole. The analysis was done by HPLC. RESULTS: It was seen that 10.36% of this population were poor metabolizers(PM) whereas 89.63% were extensive metabolizers(EM). CONCLUSION: A genotyping evaluation would better help in identifying population specific genotypes and thus help individualize drug therapy

Phosphate feeding to permit growth while maintaining secondary product synthesis

Maintaining high metabolic activities for extended periods by feeding small amounts of the growth limiting nutrient was examined for the production of cycloheximide by Streptomyces griseus . Batch studies indicated that increased initial phosphate levels led to increased cell concentrations, stimulated glucose utilization, and over a limited range (<0.6 g/l KH 2 PO 4 ) did not adversely affect cycloheximide production rates. Semi-continuous phosphate feeding was observed to permit limited cell growth, and to enhance metabolic activities (i. e. glucose utilization). The effect of semi-continuous phosphate feeding on antibiotic production depended on the feed rate, with high feed rates suppressing production.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46756/1/253_2004_Article_BF00451634.pd

Spike firing and IPSPs in layer V pyramidal neurons during beta oscillations in rat primary motor cortex (M1) in vitro

Beta frequency oscillations (10-35 Hz) in motor regions of cerebral cortex play an important role in stabilising and suppressing unwanted movements, and become intensified during the pathological akinesia of Parkinson's Disease. We have used a cortical slice preparation of rat brain, combined with concurrent intracellular and field recordings from the primary motor cortex (M1), to explore the cellular basis of the persistent beta frequency (27-30 Hz) oscillations manifest in local field potentials (LFP) in layers II and V of M1 produced by continuous perfusion of kainic acid (100 nM) and carbachol (5 µM). Spontaneous depolarizing GABA-ergic IPSPs in layer V cells, intracellularly dialyzed with KCl and IEM1460 (to block glutamatergic EPSCs), were recorded at -80 mV. IPSPs showed a highly significant (P< 0.01) beta frequency component, which was highly significantly coherent with both the Layer II and V LFP oscillation (which were in antiphase to each other). Both IPSPs and the LFP beta oscillations were abolished by the GABAA antagonist bicuculline. Layer V cells at rest fired spontaneous action potentials at sub-beta frequencies (mean of 7.1+1.2 Hz; n = 27) which were phase-locked to the layer V LFP beta oscillation, preceding the peak of the LFP beta oscillation by some 20 ms. We propose that M1 beta oscillations, in common with other oscillations in other brain regions, can arise from synchronous hyperpolarization of pyramidal cells driven by synaptic inputs from a GABA-ergic interneuronal network (or networks) entrained by recurrent excitation derived from pyramidal cells. This mechanism plays an important role in both the physiology and pathophysiology of control of voluntary movement generation

Colorful Niches of Phytoplankton Shaped by the Spatial Connectivity in a Large River Ecosystem: A Riverscape Perspective

Large rivers represent a significant component of inland waters and are considered sentinels and integrators of terrestrial and atmospheric processes. They represent hotspots for the transport and processing of organic and inorganic material from the surrounding landscape, which ultimately impacts the bio-optical properties and food webs of the rivers. In large rivers, hydraulic connectivity operates as a major forcing variable to structure the functioning of the riverscape, and–despite increasing interest in large-river studies–riverscape structural properties, such as the underwater spectral regime, and their impact on autotrophic ecological processes remain poorly studied. Here we used the St. Lawrence River to identify the mechanisms structuring the underwater spectral environment and their consequences on pico- and nanophytoplankton communities, which are good biological tracers of environmental changes. Our results, obtained from a 450 km sampling transect, demonstrate that tributaries exert a profound impact on the receiving river’s photosynthetic potential. This occurs mainly through injection of chromophoric dissolved organic matter (CDOM) and non-algal material (tripton). CDOM and tripton in the water column selectively absorbed wavelengths in a gradient from blue to red, and the resulting underwater light climate was in turn a strong driver of the phytoplankton community structure (prokaryote/eukaryote relative and absolute abundances) at scales of many kilometers from the tributary confluence. Our results conclusively demonstrate the proximal impact of watershed properties on underwater spectral composition in a highly dynamic river environment characterized by unique structuring properties such as high directional connectivity, numerous sources and forms of carbon, and a rapidly varying hydrodynamic regime. We surmise that the underwater spectral composition represents a key integrating and structural property of large, heterogeneous river ecosystems and a promising tool to study autotrophic functional properties. It confirms the usefulness of using the riverscape approach to study large-river ecosystems and initiate comparison along latitudinal gradients