James Ritchie

Antidepressant drugs with differing pharmacological actions decrease activity of locus coeruleus neurons

Previous studies suggest that all effective antidepressant (AD) drugs decrease activity of locus coeruleus (LC) neurons. However, little data exist regarding blood levels of drug in these studies, and what data do exist suggest blood levels might have been very high. To assess whether decreased LC activity is produced by drugs that selectively block reuptake for either norepinephrine or serotonin at therapeutically relevant blood levels, effects of chronic administration of desipramine, paroxetine, and escitalopram on LC activity were measured across a range of doses and blood levels of drug. Further, effects of a range of doses of mirtazapine were examined; in that mirtazapine blocks alpha2 adrenergic receptors, it might be anticipated to increase rather than decrease LC activity. Finally, to begin to assess whether the response of LC to ADs was specific to these drugs, effects of four non-AD drugs (single dose) were measured. Drugs were administered via osmotic minipump for 14 d. Electrophysiological recording of LC activity (assessment of both spontaneous firing rate and sensory-evoked burst firing) then took place under isoflurane anaesthesia on the last day of drug treatment. The blood level of drugs present at the end of the recording session was also measured. All AD drugs tested decreased LC spontaneous and sensory-evoked burst firing, and this was observed across a wide range of blood levels for the drugs. Non-AD drugs did not decrease LC activity. The findings of this investigation continue to support the possibility that all effective AD drugs decrease LC activity.

Association of relative telomere length with progression of chronic kidney disease in two cohorts: effect modification by smoking and diabetes

Chronic kidney disease (CKD) is a highly progressive disease. We studied the association between relative telomere length (RTL) and CKD progression and tested whether this association is modified by smoking and diabetes mellitus. RTL was measured by qPCR in two prospective cohort studies, the MMKD-Study (nu2009=u2009166) and the CRISIS-Study (nu2009=u2009889) with a median follow-up of 4.5 and 2.8 years, respectively. Progression was defined as doubling of baseline serum creatinine (MMKD-Study) and/or end stage renal disease (both studies). 59 and 105 of the patients from MMKD and CRISIS experienced a progression of CKD. Mean standardized pooled RTL was 0.74u2009±u20090.29. In the meta-analysis shorter RTL at baseline showed a borderline association with CKD progression (HRu2009=u20091.07 [95%CI 1.00–1.15]; pu2009=u20090.06). We observed an effect modification of RTL and CKD progression by smoking and diabetes (p-values of interaction pu2009=u20090.02 and pu2009=u20090.09, respectively). Each 0.1 unit shorter RTL was significantly associated with an increased hazard for CKD progression in active-smokers by 44% (HRu2009=u20091.44 [1.16–1.81]; pu2009=u20090.001) and in patients with diabetes mellitus by 16% (HRu2009=u20091.16 [1.01–1.34]; pu2009=u20090.03). Estimates were adjusted for baseline age, sex, proteinuria and GFR. This study in two independent cohorts reinforces that RTL is a marker and potentially a pathogenetic factor for CKD progression.

Influence of chronic administration of antidepressant drugs on mRNA for galanin, galanin receptors, and tyrosine hydroxylase in catecholaminergic and serotonergic cell-body regions in rat brain

Activity of locus coeruleus (LC) neurons and release of the peptide galanin (GAL), which is colocalized with norepinephrine (NE) in LC neurons, has been implicated in depression and, conversely, in antidepressant action. The present study examined the influence of chronic administration (for 14days, via subcutaneously-implanted minipump) of antidepressant (AD) drugs representing three different classes (tricyclic [desipramine], selective serotonin reuptake inhibitor [SSRI] [paroxetine], and monoamine oxidase inhibitor [MAOI] [phenelzine]) on mRNA for GAL, GAL receptors (GalR1, GalR2, and GalR3), and tyrosine hydroxylase (TH), the rate-limiting enzyme for NE synthesis, in four brain regions--LC, A1/C1, dorsal raphe (DRN), and ventral tegmentum (VTA) of rats. Consistent with previous findings that chronic administration of AD drugs decreases activity of LC neurons, administration of AD drugs reduced mRNA for both GAL and TH in LC neurons. GAL and TH mRNA in LC neurons was highly correlated. AD drugs also reduced GAL and TH mRNA in A1/C1 and VTA but effects were smaller than in LC. The largest change in mRNA for GAL receptors produced by AD administration was to decrease mRNA for GalR2 receptors in the VTA region. Also, mRNA for GalR2 and GalR3 receptors was significantly (positively) correlated in all three predominantly catecholaminergic brain regions (LC, A1/C1, and VTA). Relative to these three brain regions, unique effects were seen in the DRN region, with the SSRI elevating GAL mRNA and with mRNA for GalR1 and GalR3 being highly correlated in this brain region. The findings show that chronic administration of AD drugs, which produces effective antidepressant action, results in changes in mRNA for GAL, GAL receptors, and TH in brain regions that likely participate in depression and antidepressant effects.

Paroxetine-Induced Increase in Activity of Locus Coeruleus Neurons in Adolescent Rats: Implication of a Countertherapeutic Effect of an Antidepressant

The concern that antidepressant (AD) drugs, especially selective serotonin reuptake inhibitors and paroxetine (PAR) in particular, can increase suicidality during the early treatment of juvenile patients (children and adolescents) has created a dilemma for clinicians treating depressives. Although preclinical research cannot resolve controversy in this area, our present findings may provide insight into how AD drugs might, under certain conditions, exacerbate rather than ameliorate the depressive state. Both clinical and preclinical evidences indicate that the principal noradrenergic cell group in the brain, the locus coeruleus (LC), is overactive in depressives and that, conversely, effective AD treatments decrease the activity of LC neurons. We report here that short-term (2 and 4 days) administration of PAR produces an increase in the activity of LC neurons (spontaneous firing rate and sensory-evoked responses) in young rats, contrary to the ‘therapeutic decrease in activity typically observed in adult rats. Blood levels of PAR were lower in young rats than in adult rats, although similar low blood levels produced by a lower dose of PAR in adult rats failed to produce an increase in LC activity. In addition, activity of young rats in the swim test was determined to assess depressive-like responses. The same dose/durations of PAR, which produced the largest increases in LC activity in young rats, produced decreases in swim-test activity, indicating that brief administration of PAR in young rats can promote, rather than reduce, the depressive state. These results offer a model that may help screen potential adjunctive treatments to avoid early adverse effects of ADs.

Model-based lamotrigine clearance changes during pregnancy: clinical implication

The objective of the study was to characterize changes in the oral clearance (CL/F) of lamotrigine (LTG) over the course of pregnancy and the postpartum period through a model‐based approach incorporating clinical characteristics that may influence CL/F, in support of developing clinical management guidelines.

Immune Activation Mediated Change in Alpha‐1‐Acid Glycoprotein: Impact on Total and Free Lopinavir Plasma Exposure

Background: Immune mediated changes in circulating α‐1‐acid glycoprotein (AAG), a type 1 acute phase protein, which binds protease inhibitors (PI), may alter protein binding and contribute to PIs pharmacokinetic (PK) variability. Methods: In a prospective, 2‐phase intensive PK study on antiretroviral naive human immunodeficiency virus (HIV)‐infected subjects treated with a lopinavir‐/ritonavir‐based regimen, steady state PK sampling and AAG assays were performed at weeks 2 and 16 of treatment. Results: Median entry age was 43 years (n = 16). Median plasma log10 HIV‐1 RNA, CD4 T‐cell counts, and AAG were 5.16 copies/mL, 28 cells/μL, and 143 mg/dL, respectively. The total lopinavir area under the concentration time curve (AUC12_total) and maximum concentration (Cmax_total) changed linearly with AAG at mean rates of 16±7 mg*hr/L (slope ± SE); P = .04, and 1.6 ± 0.6 mg/L, P = .02, per 100 mg/dL increase in AAG levels, respectively (n = 15).A 29% drop in AAG levels between week 2 and week 16 was associated with 14% (geometric mean ratio [GMR] = 0.86; 90% confidence interval [CI] = 0.74–0.98) and 13% (GMR = 0.87; 90% CI = 0.79–0.95) reduction in AUC12_total and Cmax_total, respectively. Neither free lopinavir PK parameters nor antiviral activity (HIV‐1 RNA average AUC minus baseline) was affected by change in plasma AAG. Conclusions: Changes in plasma AAG levels alter total lopinavir concentrations, but not the free lopinavir exposure or antiviral activity. This observation may have implications in therapeutic drug monitoring.

Where now in the management of renal artery stenosis? Implications of the ASTRAL and CORAL trials.

Purpose of reviewThe neutral findings of Angioplasty and Stenting for Renal Artery Lesions and Cardiovascular Outcomes in Renal Artery Lesions trials have shown that unselected revascularization does not improve outcomes in atherosclerotic renovascular disease (ARVD). This review highlights recent translational, clinical and epidemiological studies and suggests directions for future research. Recent findingsImaging studies show that the degree of renal artery stenosis is not the most important determinant of outcome and response to therapies in ARVD. Porcine models have established a better understanding of the microvascular and inflammatory changes that occur in ARVD. Biomarkers of inflammation and cardiovascular dysfunction may be informative but do not yet help assess prognosis or response to treatment. Stem cell therapies show promise in animal models but have yet to translate into clinical practice. Analysis of patient subgroups with high-risk presentations of ARVD has provided new insights into treatment response and may guide future studies. SummaryIt is time to reframe thinking and research in ARVD. We need better ways to identify patients likely to benefit from revascularization and to improve response to treatment in these individuals. Many preclinical studies show promise, but these are often small scale and difficult to replicate. Future work should focus on establishing an international disease registry as a foundation for collaborative research.

The DREADD agonist clozapine N -oxide (CNO) is reverse-metabolized to clozapine and produces clozapine-like interoceptive stimulus effects in rats and mice

Clozapine-N-oxide (CNO) has long been the ligand of choice for selectively activating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). However, recent studies have challenged the long-held assertion that CNO is otherwise pharmacologically inert. The present study aimed to 1) determine whether CNO is reverse-metabolized to its parent compound clozapine in mice (as has recently been reported in rats), and 2) determine whether CNO exerts clozapine-like interoceptive stimulus effects in rats and/or mice. Following administration of 10.0u2009mg/kg CNO, pharmacokinetic analyses replicated recent reports of back-conversion to clozapine in rats and revealed that this phenomenon also occurs in mice. In rats and mice trained to discriminate 1.25u2009mg/kg clozapine from vehicle, CNO (1.0–20.0u2009mg/kg) produced partial substitution for the clozapine stimulus on average, with full substitution being detected in some individual animals of both species at doses frequently used to activate DREADDs. The present demonstration that CNO is converted to clozapine and exerts clozapine-like behavioral effects in both mice and rats further emphasizes the need for appropriate control groups in studies employing DREADDs, and highlights the utility of the drug discrimination procedure as a tool with which to screen the off-target effects of novel DREADD agonists.

Three Decades of Atherosclerotic Reno-vascular Disease Management - Changing Outcomes in an Observational Study.

Background/Aims: Optimized medical therapy has improved cardiovascular outcomes in the general population. To investigate whether changes in the management of atherosclerotic renovascular disease (ARVD) have had an impact on clinical outcomes. Methods: Recruitment into this single-center prospective cohort study started in 1986. Data was analyzed retrospectively. Patients were divided into four groups based on relationship of diagnosis year to landmark randomized controlled trials (RCT); group 1 - pre-large RCT data (1986-2000); group 2 - post-early RCT (2001-2004); group 3 - ASTRAL study recruitment era (2004-2009); group 4 - post-ASTRAL (2009-2014). Results: In total, 872 patients were followed for a median 54.9 months (IQR 20.2-96.2). Over successive time-periods, there was an increase in baseline utilization of renin angiotensin blockade (RAB) (group 4: 69% vs. group 1: 31%, p<0.001), statins (74% vs 20%, p<0.001) and beta-blockers (43% vs 30%, p=0.024). Median time to death, end-stage kidney disease and cardiovascular events improved except in group 4, which displayed more baseline cardiovascular comorbidities. The number of investigative angiograms performed decreased from 139 per year between 2006 and 2008 to 74 per year in group 4. Conclusions: Although fewer patients are being investigated for ARVD in our center, these have more cardiovascular comorbidities. Nonetheless, optimized medical therapy may have contributed towards improved proteinuria, renal function and clinical outcomes in patients diagnosed with ARVD.

Locus coeruleus neuronal activity determines proclivity to consume alcohol in a selectively-bred line of rats that readily consumes alcohol

Sprague-Dawley rats selectively-bred for susceptibility to stress in our laboratory (Susceptible, or SUS rats) voluntarily consume large amounts of alcohol, and amounts that have, as shown here, pharmacological effects, which normal rats will not do. In this paper, we explore neural events in the brain that underlie this propensity to readily consume alcohol. Activity of locus coeruleus neurons (LC), the major noradrenergic cell body concentration in the brain, influences firing of ventral tegmentum dopaminergic cell bodies of the mesocorticolimbic system (VTA-DA neurons), which mediate rewarding aspects of alcohol. We tested the hypothesis that in SUS rats alcohol potently suppresses LC activity to markedly diminish LC-mediated inhibition of VTA-DA neurons, which permits alcohol to greatly increase VTA-DA activity and rewarding aspects of alcohol. Electrophysiological single-unit recording of LC and VTA-DA activity showed that in SUS rats alcohol decreased LC burst firing much more than in normal rats and as a result markedly increased VTA-DA activity in SUS rats while having no such effect in normal rats. Consistent with this, in a behavioral test for reward using conditioned place preference (CPP), SUS rats showed alcohol, given by intraperitoneal (i.p.) injection, to be rewarding. Next, manipulation of LC activity by microinfusion of drugs into the LC region of SUS rats showed that (a) decreasing LC activity increased alcohol intake and increasing LC activity decreased alcohol intake in accord with the formulation described above, and (b) increasing LC activity blocked both the rewarding effect of alcohol in the CPP test and the usual alcohol-induced increase in VTA-DA single-unit activity seen in SUS rats. An important ancillary finding in the CPP test was that an increase in LC activity was rewarding by itself, while a decrease in LC activity was aversive; consequently, effects of LC manipulations on alcohol-related reward in the CPP test were perhaps even larger than evident in the test. Finally, when increased LC activity was associated with (i.e., conditioned to) i.p. alcohol, subsequent alcohol consumption by SUS rats was markedly reduced, indicating that SUS rats consume large amounts of alcohol because of rewarding physiological consequences requiring increased VTA-DA activity. The findings reported here are consistent with the view that the influence of alcohol on LC activity leading to changes in VTA-DA activity strongly affects alcohol-mediated reward, and may well be the basis of the proclivity of SUS rats to avidly consume alcohol.