Auditory mismatch responses are differentially sensitive to changes in muscarinic acetylcholine versus dopamine receptor function

The auditory mismatch negativity (MMN) has been proposed as a biomarker of NMDA receptor (NMDAR) dysfunction in schizophrenia. Pathophysiological theories suggest that such dysfunction might be partially caused by aberrant interactions of different modulatory neurotransmitters with NMDARs, which could explain heterogeneity among patients with schizophrenia and their treatment response. Understanding the differential impact of different neuromodulators on readouts of NMDAR function is therefore of high clinical relevance.Here, we report results from two studies (N=81 each) which systematically tested whether the MMN is sensitive to diminishing and enhancing cholinergic vs. dopaminergic function. Both studies used a double-blind, placebo-controlled between-subject design and monitored individual drug plasma levels. Using a novel variant of the auditory oddball paradigm, we contrasted phases with stable versus volatile probabilities of tone switches. In the first study, we found that the muscarinic acetylcholine receptor antagonist biperiden reduced mismatch responses, particularly during stable phases of the experiment, whereas this effect was absent for amisulpride, a dopamine D2/D3 receptor antagonist. The direct comparison between biperiden and amisulpride indicated a significant drug × mismatch interaction. In the second study, neither elevating acetylcholine nor dopamine levels via administration of galantamine and levodopa, respectively, exerted significant effects on MMN.Overall, our results indicate differential sensitivity of the MMN to changes in cholinergic (muscarinic) versus dopaminergic receptor function. This finding may prove useful for developments of future tools for predicting individual treatment responses in disorders that show abnormal MMN, such as schizophrenia.

One-year prospective nerve conduction study of thalidomide neuropathy in lupus erythematosus: Incidence, coasting effect and drug plasma levels

Background Few prospective studies in cutaneous and systemic lupus erythematosus (CLE/SLE) assessed thalidomide-induced peripheral neuropathy (TiPN) incidence/reversibility, and most have not excluded confounding causes neither monitored thalidomide plasma levels. Objectives To evaluate TiPN incidence/reversibility, coasting effect and its association with thalidomide plasma levels in CLE/SLE. Methods One-year prospective study of thalidomide in 20 CLE/SLE patients without pregnancy potential, with normal nerve conduction study (NCS), and excluded other PN causes. Thalidomide levels were determined by high-performance liquid chromatography/tandem mass spectrometry. Results Twelve patients (60%) developed TiPN: 33.3% were symptomatic and 66.6% asymptomatic. Half of this latter group developed coasting effect (TiPN symptoms 1-3 months after drug withdrawal). The main predictive factors for TiPN were treatment duration ≥6 months (p = 0.025) and cumulative dose (p = 0.023). No difference in plasma thalidomide levels between patients with/without TiPN was observed (p = 0.464). After drug withdrawal, 75% symptomatic TiPN patients improved their symptoms. Seven TiPN patients underwent an additional NCS after drug withdrawal: 42.8% worsened NCS, 14.2% was stable, and 42.8% had improved NCS. Conclusion Our data provides novel evidence of coasting effect in half of asymptomatic patients with TiPN. The irreversible nature of this lesion in 25% of TiPN patients reinforces the relevance of early NCS monitoring, and suggests thalidomide use solely as a bridge for other effective therapy for refractory cutaneous lupus patients.

Late Pulmonary Embolism after COVID-19 Pneumonia despite Adequate Rivaroxaban Treatment

Introduction: SARS-CoV-2 infection may predispose patients to thrombotic disease. Patients with COVID-19 pneumonia who are receiving non-vitamin K antagonists or direct oral anticoagulants for chronic disease are usually switched to heparin treatment during hospitalization. However, information about the most appropriate antithrombotic therapy after the acute infection phase is lacking. Case Description: We report the case of a patient with chronic atrial fibrillation who was recently hospitalized for severe COVID-19 pneumonia. Four weeks after discharge he experienced an episode of an acute pulmonary embolism while on rivaroxaban therapy with adequate drug plasma levels, and in the absence of strong predisposing risk factors. Conclusion: This case highlights the risk of thrombotic complications after COVID-19 infection, raises some concern about their underlying mechanisms, and supports the use of effective anti-thrombotic therapy.

Paliperidone LAI and Aripiprazole LAI Plasma Level Monitoring in the Prophylaxis of Bipolar Disorder Type I with Manic Predominance

Introduction The objective of this study was the evaluation of utility of plasma level monitoring in the clinical stabilizing efficacy and tolerability of paliperidone palmitate (PP) vs. aripiprazole monohydrate (AM) in bipolar disorder I (BD I) with manic predominance. Methods Fifty-six outpatients of both sexes, age ranging from 18 to 65 years, affected by BD I with manic predominance, orally treated and stabilized after acute episode for at least 2 weeks with paliperidone or aripiprazole (n=31, paliperidone; n=25, aripiprazole) underwent a prospective observational study of switching to the corresponding long-acting injection (LAI) on the basis of clinical evaluation. The efficacy and tolerability of the 2 treatments were assessed by BPRS, PANSS, HAMD21, and MRS rating scales and a check list every month for 12 months. Drug plasma levels determinations (PLs) were performed at the same times. Results A good clinical stability and tolerability of both drugs were reported. Lower mean PLs of PP showed a positive effect on depressive symptoms. AM PLs variability was associated with greater instability of manic symptoms whereas intermediate PLs seem to have more influence on depressive symptomatology. Discussion PLs drug monitoring has been proven to be useful, and further investigations to identify optimal therapeutic ranges for LAI formulations are needed.

Nanostructured lipid carriers with ultra purified lipids for sustained release of intravenous lidocaine

Lidocaine (LDC) is a local anesthetic that can be used for post-surgical or cancer related pain, via intravenous infusion or bolus. An alternative to maintain drug plasma levels are the sustained release carriers, whereas nanostructured lipid carriers (NLCs) stand out; they have biocompatibility, low toxicity, reproducibility and high efficiency in the transport of hydrophobic drugs.This work aims to study the solubility parameter of the LDC pre formulation in several ultra-purified lipids, compatible with the endovenous route, and to formulate NLCs based on these lipids for LDC encapsulation.

Methylphenidate challenge followed by therapeutic drug monitoring in adults with attention deficit/hyperactivity disorder: Clinical effects and its predictors

IntroductionAttention deficit/hyperactivity disorder (ADHD) affects 5–6% of adults. Methylphenidate challenge is used to test functions such as concentration. Therapeutic drug monitoring (TDM) identifies optimal drug ranges in plasma.Objectives/AimsWe aimed to: assess the clinical impact of the drug challenge in adults with ADHD; analyze the relationship with the drug plasma levels after the challenge; identify predictors of the challenge's clinical impact.MethodsIn 2015–2016, we recruited 45 consecutive adult DSM-5 ADHD outpatients (mean age ± SD = 35.3 ± 2.1 years; females = 64.4%) at the Bolzano hospital department of psychiatry. Before and after administration of methylphenidate 10 mg, we measured concentration, impulsivity, tension, and general well-being with a VAS and an interview. After two hours, TDM was performed. Deltas were calculated for pre-/post-challenge measures. Correlations were measured with Pearson's r/point-biserial coefficient. A generalized linear mixed model estimated the size of association between tension/general well-being improvement and patient characteristics.ResultsAfter the challenge, the mean improvement ± SD was 24 ± 22 for concentration, 17 ± 23 for impulsivity, 21 ± 28 for tension, 16 ± 24 for general well-being. The mean TDM ± SD was 4.6 ± 0.5 ng/mL. A negative correlation between TDM, tension (P = 0.009), and general well-being (P = 0.028) after the challenge emerged: higher drug plasma levels relate to less tension and greater general well-being. At the GLMM the main predictor for tension/general well-being improvement was psychopharmacological treatment (P = 0.011/P = 0.05, respectively). Older age and difficult tasks prevented improvement.ConclusionsMethylphenidate challenge had a positive effect on all patients’ performance. TDM values were lower than literature ones, although the latter are usually obtained after the administration of methylphenidate 20 mg.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Opioid Addiction: Social Problems Associated and Implications of Both Current and Possible Future Treatments, including Polymeric Therapeutics for Giving Up the Habit of Opioid Consumption

Background. Detoxification programmes seek to implement the most secure and compassionate ways of withdrawing from opiates so that the inevitable withdrawal symptoms and other complications are minimized. Once detoxification has been achieved, the next stage is to enable the patient to overcome his or her drug addiction by ensuring consumption is permanently and completely abandoned, only after which can the subject be regarded as fully recovered. Methods. A systematic search on the common databases of relevant papers published until 2016 inclusive. Results and Conclusion. Our study of the available oral treatments for opioid dependence has revealed that no current treatment can actually claim to be fully effective. These treatments require daily oral administration and, consequently, regular visits to dispensaries, which in most cases results in a lack of patient compliance, which causes fluctuations in drug plasma levels. We then reviewed alternative treatments in the available scientific literature on polymeric sustained release formulations. Research has been done not only on release systems for detoxification but also on release systems for giving up the habit of taking opioids. These efforts have obtained the recent authorization of polymeric systems for use in patients that could help them to reduce their craving for drugs.

Performance of coagulation tests in patients on therapeutic doses of rivaroxaban

SummaryKnowledge of anticoagulation status during rivaroxaban therapy is desirable in certain clinical situations. It was the study objective to determine coagulation tests most useful for assessing rivaroxaban’s anticoagulant effect. Peak and trough blood samples from 29 patients taking rivaroxaban 20 mg daily were collected. Mass spectrometry and various coagulation assays were performed. “On-therapy range” was defined as the rivaroxaban concentrations determined by LC-MS/ MS. A “misprediction percentage” was calculated based on how often results of each coagulation assay were in the normal reference range, while the rivaroxaban concentration was in the “on-therapy” range. The on-therapy range was 8.9 – 660 ng/ml. The misprediction percentages for prothrombin time (PT) and activated partial thromboplastin time (aPTT), using multiple reagents and coagulometers, ranged from 10% – 52% and 31% – 59%, respectively. PT, aPTT and activated clotting time (ACT) were insensitive to trough rivaroxaban: 59%, 62%, and 80% of samples had a normal result, respectively. Over 95% of PT and ACT values were elevated at peak. Four different rivaroxaban calibrated anti-Xa assays had R2 values >0.98, demonstrating strong correlations with rivaroxaban drug levels. In conclusion, PT, aPTT and ACT are often normal in patients on therapeutic doses of rivaroxaban. However, PT and ACT may have clinical utility at higher drug plasma levels. Rivaroxaban calibrated anti-factor Xa assays can accurately identify low and high on-therapy rivaroxaban drug levels and, therefore, have superior utility in all clinical situations where assessment of anticoagulation status may be beneficial.This trial is registered at www.clinicaltrials.gov (#NCT01743898).

Effect of catechol-O-methyltransferase Val(108/158)Met polymorphism on antidepressant efficacy of fluvoxamine

RationaleThe catechol-O-methyltransferase (COMT) enzyme inactivates catecholamines, and the COMT Val(108/158)Met polymorphism (rs4680) influences the enzyme activity. Recent clinical studies found a significant effect of rs4680 on antidepressant response to fluoxetine and paroxetine, but several other studies were negative. No study considered drug plasma levels as possible nuisance covariate.ObjectivesWe studied the effect of rs4680 on response to fluvoxamine antidepressant monotherapy.Patients and methodsForty-one consecutively admitted inpatients affected by a major depressive episode in course of major depressive disorder were administered fluvoxamine for 6 weeks. Changes in severity of depression were assessed with weekly Hamilton Depression ratings and analyzed with repeated measures ANOVA in the context of General Linear Model, with rs4680 and fluvoxamine plasma levels as factors.Resultsrs4680 significantly interacted with time in affecting antidepressant response to fluvoxamine, with outcome being inversely proportional to the enzyme activity: better effects in Met-carriers, worse effects in Val/Val homozygotes. The effect became significant at the fourth week of treatment, and influence final response rates. Fluvoxamine plasma levels had marginal effects on outcome.ConclusionsThis is the first study that reports a positive effect of rs4680 on response to fluvoxamine, and the third independent report of its influence on response to selective 5-HT reuptake inhibitors (SSRIs). Our findings support the hypothesis that factors affecting catecholaminergic neurotransmission might contribute to shape the individual response to antidepressants irrespective of their primary molecular target.