Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation - Clinical and safety results.

INTRODUCTION: We investigated the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in patients suffering from treatment-resistant depression (TRD) as add-on therapy. MATERIAL AND METHODS: Patients were randomized to an additional 160 mg/day or 240 mg/day KET01 or placebo for 14 days. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. For treatment group comparisons, we used ANOVA with pairwise least squares mean difference tests in a mixed model repeated measures analysis. RESULTS: Twenty-seven patients completed the double-blind protocol before trial premature termination due to poor recruitment during the COVID-19 pandemic. Mean (SD) MADRS scores on day 15 were 23 (10.32) in placebo, 25 (8.28) with 160 mg/day and 17 (10.32) with 240 mg/day KET01. MADRS change was numerically larger but statistically non-significant in the 240 mg/day KET01 group vs placebo on day 7 (-5.67; p = 00.106) and day 15 was (difference: 4.99; p = 00.15). In exploratory analysis, baseline leukocyte count correlated with response to KET01 (p = 00.01). Distribution of adverse event rates were comparable between the treatment arms. Safety analysis did not identify increased risk of suicidality, dissociation, hear rate, systolic and diastolic blood pressure associated with trial treatment. DISCUSSION: Our results suggest that adjunctive oral administration of prolonged-release ketamine at a dose of 240 mg/day shows a positive, although statistically non-significant, trend towards antidepressant efficacy, however, the benefit could not be confirmed due to premature trial termination. Given its ease of use and low side effects, further trials are warranted to investigate this route of ketamine administration as a promising potential treatment of TRD.

Current Findings and Mechanisms of Action of Disulfiram in the Treatment of Alcohol Dependence.

As an alcohol-aversive agent, disulfiram occupies an exceptional position in the pharmacological relapse prevention of alcohol dependence. In contrast to anti-craving drugs, disulfiram does not modulate neurobiological mechanisms of addiction, but rather works by producing an aversive reaction when combined with alcohol. Therapeutic and adverse effects are therefore closely related: On the one hand, the aversiveness of the disulfiram ethanol reaction has the potential to support abstinence in a subgroup of alcohol-dependent patients, while on the other hand it becomes a health threat if the patient fails to maintain complete abstinence. The exceptional position of disulfiram is also related to the role that expectations play in the mediation of therapeutic effects. These are not determined by the pharmacological effects or the actual occurrence of a disulfiram-ethanol reaction, but are attributable to patient awareness that the drug was consumed and the corresponding anticipation of an aversive reaction if combined with alcohol. This is in line with the findings of a recent meta-analysis that only showed significant effects for disulfiram in open-label trials. The authors of the meta-analysis conclude that due to expectations induced in both the treatment and placebo groups, blinded studies are incapable of distinguishing a difference between groups. The mediation of therapeutic effects through expectation has a number of consequences for clinical practice and future research on disulfiram.

Intraperitoneal atrial natriuretic peptide attenuates anxiety-related behaviour during alcohol withdrawal in mice.

Converging evidence from both preclinical and clinical studies suggests atrial natriuretic peptide (ANP) as a potential target for treatment of alcohol withdrawal and dependence. Since ANP tightly interacts with hypothalamic-pituitary-adrenocortical (HPA) axis activity, especially the modulation of stress-related anxiety during alcohol withdrawal might mediate these effects. We have now evaluated the anxiolytic activity of intraperitoneal ANP application during alcohol withdrawal in alcohol-habituated mice (C57/Bl6J). Anxiety related behaviour was attenuated during ethanol withdrawal following application of ANP (60 µg/kg) vs. saline. Our results support that anxiolytic effects of ANP mediate ANP-related gene effects with clinical data on withdrawal symptomatology.

Rivastigmine reduces tobacco craving in alcohol-dependent smokers.

INTRODUCTION: Although alcohol-dependent smokers represent an important group for applying smoking interventions, a sufficient pharmacotherapy has not been established in this high-risk group so far. METHODS: In order to examine the effect of the acetylcholinesterase inhibitor rivastigmine on tobacco dependence, we performed a 12-week, randomized, placebo-controlled trial. 26 alcohol-dependent smokers were randomized to rivastigmine 6 mg/day (n=14) or placebo (n=12). Assessments on addictive behavior included carbon monoxide (CO), severity of tobacco dependence (FTND), daily smoked cigarettes (diaries), and craving for tobacco (QSU) and alcohol (AUQ). RESULTS: ANOVA revealed a significant treatment-by-time interaction for tobacco consumption and tobacco craving (each p<0.0001). The rivastigmine group showed a decrease in daily smoked cigarettes (-30%), in exhaled carbon monoxide (-32%) and in tobacco craving (-18%) whereas controls did not show significant changes. ANCOVA revealed rivastigmine effects to be more prominent in smokers suffering from more severe tobacco dependence. None of the patients developed an alcohol relapse or an increase in alcohol craving. DISCUSSION: Our preliminary data indicate an effect of rivastigmine on tobacco craving and consumption. This pilot study encourages further investigation of acetylcholinesterase-inhibitors as a promising treatment approach regarding tobacco dependence.

[Myeloablative radioimmunotherapy with 188Re-CD66mAb before stem cell transplantation. No increase of proinflammatory cytokine levels of TNF-alpha]. / Myeloablative Radioimmuntherapie mit 188Re-CD66mAb vor Stammzelltransplantation: Kein Anstieg proinflammatorischer Zytokinspiegel von TNF-alpha.

AIM: Tumour necrosis factor-alpha (TNF-alpha) serum levels may increase due to intensive conditioning regimes with high-dose-chemotherapy and total body irradiation (TBI) before stem cell transplantation. This increases the risk for developing acute graft versus host disease (aGvHD) after stem cell transplantation. In this prospective study we investigated the influence of radioimmunotherapy with 188Re-CD-66-mAb on changes on TNF-alpha serum levels. PATIENTS, METHODS: In 18 patients we measured TNF-alpha before and up to 96 hours after radioimmunotherapy, in 2 patients in addition following TBI, in 9 patients also following chemotherapy. For measuring TNF-alpha we used an automated immunochemiluminescence assay (Immulite 1000 DPC Biermann, Bad Nauheim). The mean follow up period to record incidence of aGVHD was 100 days after stem cell transplantation. RESULTS: Compared to the basal levels before, the levels of TNF-alpha after conditioning with 188Re-CD-66-mAb did not increase significantly and remained in the physiological range. In contrast, these initial physiological cytokine levels increased and became pathological following 48 h after total body irradiation (13.2+/-6.6 pg/ml) and chemotherapy (10.8+/-15.7 pg/ml). In our study we found a low incidence of aGvHD (22.2%, n=4/18). CONCLUSION: These results demonstrate that additional conditioning therapy with 188Re-CD-66-mAb does not increase proinflammatory cytokine levels of TNF-alpha. This finding may indicate that additive radioimmunotherapy may not be a significant factor for increasing the rate of conditioning-associated aGvHD.

[Pharmacology of disulfiram - an update]. / Klinische Pharmakologie von Disulfiram - eine aktuelle Ubersicht1.

Recently, we have been observing an increase in prescription of Disulfiram requiring medical knowledge concerning the overall effects, side effects and drug interactions of this substance. In the following report, we give an overview about the pharmacology and the side effects of Disulfiram. As an example we demonstrate a case, in which an acute neurological deficit was misjudged as a side effect of Disulfiram. Furthermore, the potential of Disulfiram as a promising treatment in addiction medicine will be discussed.

[Illegal purchase of psychotropic drugs from the internet]. / Beschaffung psychotroper Substanzen über das Internet.

Several national institutions are registering a significant increase in sales of prescription and illegal drugs from internet pharmacies. Psychoactive drugs are preferred; the clients are particularly young. Considering the current amount of data available, the extent and relevance to addiction medicine remain unclear. In the following report we present the case of a patient from our outpatient department who has suffered from an opioid dependency for several years and has been using a Spanish internet pharmacy to purchase tramadol without prescription.

[Psychotic symptoms in a case of locked-in syndrome]. / Psychotische Symptome beim Locked-in-Syndrom.

In this case report we describe a patient who suffered brainstem bleeding mainly in the pons and mesencephalon leading to locked-in syndrome. During rehabilitation she suffered psychotic symptoms of threatening character. Due to location of the lesion and the coincidental appearance of the bleeding, we diagnosed an organic psychosis. After treatment with the atypical neuroleptic drug Quetiapine, the symptoms decreased, facilitating the patient's rehabilitation course.

Acylated fibronectin: a new type of posttranslational modification of cellular fibronectin.

Human fibroblasts were labelled with either [35S]methionine or [3H]palmitate and analyzed for the presence of 35S- or 3H-labelled fibronectin by immunoprecipitation and SDS-polyacrylamide gel electrophoresis. The majority of 35S-labelled fibronectin was found in the extracellular matrix of cells which could be removed quantitatively by mild trypsin treatment. In contrast, 3H-labelled fibronectin was found in a trypsin-resistant form. The 3H label of fibronectin could be identified predominantly as [3H]palmitate by HLPC analysis. The fatty acids remained stably associated with fibronectin during extraction and electrophoresis, indicating a covalent linkage. These results demonstrate that a subset of fibronectin different from extracellular matrix fibronectin is modified by acylation.

Cell surface binding simian virus 40 large T antigen becomes anchored and stably linked to lipid of the target cells.

Previously a new small subclass of SV40 large T antigen with a high-binding affinity to living target cells was characterized (J. Lange-Mutschler and R. Henning, 1983, Virology 127, 333-344.) In the present study the external binding process, particularly the tight linkage of T antigen to lipid of the target cells, was analyzed. Extraction of SV40-transformed target cells (SV80) first by sonification yielded approx 80% of [35S]methionine-labeled T antigen (mechanical extract). A further 20% was obtained by treatment of cellular debris with hydroxylamine (hydroxylamine extract). As shown by an 125I-protein A radioimmunoassay, hydroxylamine extracts contained significantly higher amounts of cell surface binding T antigen. Correspondingly, after incubating [3H]palmitic acid-prelabeled target cells (HeLa) with unlabeled extracts, predominantly T antigen from hydroxylamine extracts became 3H labeled by the target cells, dependent on metabolic or enzymatic conditions. 3H-labeled T antigen became unlabeled after treatment with hydroxylamine indicating a covalent ester linkage between cell surface-bound T antigen and lipid of the target cells. The cell surface localization of in vitro acylated T antigen was demonstrated by mild trypsin digestion of living target cells. These results strongly support the idea about a novel mechanism by which a minor subclass of T antigen after being bound to the cell surface becomes covalently linked to lipid of the living cell.

Tightly associated lipids may anchor SV40 large T antigen in plasma membrane.

Simian virus 40 (SV40) large T antigen, a multifunctional protein necessary for lytic growth and cell transformation, is located mainly in the nucleus and in small amounts on the cell surface (surface T). Surface T may have a passive role in SV40 tumour rejection by cytotoxic T cells as a component of SV40-TSTA (tumour-specific transplantation antigen). The unusual induction of this immune response by immunizing mice with soluble T antigen led us to investigate the in vitro binding of T antigen to the surface of living cells in more detail. Our results show that native surface T and a minor subset of large T antigen having a high cell surface binding affinity in vitro, behave like integral membrane proteins. Several viral proteins including SV40 T antigen and cellular proteins seem to be linked to fatty acids (acylation). To analyse whether this mechanism is involved in the stable attachment of in vitro-bound T antigen to the plasma membrane of living target cells, we determined the degree of labelling of this molecule by using target cells prelabelled with 3H-fatty acid. Here we report that T antigen extracted from unlabelled SV40-transformed cells (SV80) becomes 3H-labelled after in vitro binding to the cell surface of 3H-palmitate-prelabelled HeLa cells. These results suggest that T antigen attached externally to living cells, may be anchored by tightly linked lipids.

A subclass of simian virus 40 T antigen with a high cell surface binding affinity.

SV40 virus-infected and -transformed cells express large T antigen on the cell surface (surface T). In the present study the cell surface binding properties of T antigen extracted from SV40-transformed cells were investigated. Only small amounts of T antigen with tight cell surface binding properties were efficiently removable by absorption on living cells from the majority of T antigen detectable in cell extracts. As shown in immunofluorescence microscopy both native surface T and experimentally in vitro cell surface bound T antigen were stained in similar microcluster patterns. Comparative SDS-polyacrylamide gel electrophoretic analysis indicated that T antigen extracted from SV40-transformed cells and in vitro cell surface bound T antigen had the same apparent molecular weight of approximately 90,000 da. A quantitative 125I-protein A binding assay using antisera directed against purified T antigen demonstrated that a metal-ion chelating agent (EDTA) or hypertonic salt solutions were unable to remove surface T or in vitro cell surface bound T antigen from living cells. In contrast, both antigens could be solubilized by detergents. Moreover, both types of cell surface associated T antigens seemed to be metabolically stable. Altogether, one can postulate a minor subclass of T antigen with a tight binding affinity to the cell surface of living cells. According to these properties this experimentally membrane bound subclass, as well as native surface T, seem to belong to the class of integral rather than peripheral membrane proteins.