Applications of alcohol clamping in early drug development

This thesis describes the development of a novel alcohol clamp, a new method to obtain stable plasma levels of alcohol and its application in CNS-research. The method might have several advantages that were explored in subsequent studies described in this thesis. The stability of the alcohol clamp was used to examine functional effect profiles and time-dependence of different CNS-effects. The tests to examine these effects were chosen based upon a prior review of the literature, during which the most sensitive CNS-tests were selected. Hereafter, we studied the alcohol clamping method as a tool to compare alcohol disposition capacities between different (ethnic) populations and as a tool to compare their different CNS-responses to multiple stable alcohol levels. We also investigated whether the clamping method could be useful as a future benchmarking entity in CNS-research, based on its fMRI effects on the brain at rest and its efficacy on tremor symptoms. Finally, we employed the method in an interaction study with a compound that is in development for addictive disorders including alcoholism. This thesis has examined several examples of situations where the alcohol clamp has been a useful research instrument during alcohol research and in early drug development.UBL - phd migration 201

Applications of alcohol clamping in early drug development

This thesis describes the development of a novel alcohol clamp, a new method to obtain stable plasma levels of alcohol and its application in CNS-research. The method might have several advantages that were explored in subsequent studies described in this thesis. The stability of the alcohol clamp was used to examine functional effect profiles and time-dependence of different CNS-effects. The tests to examine these effects were chosen based upon a prior review of the literature, during which the most sensitive CNS-tests were selected. Hereafter, we studied the alcohol clamping method as a tool to compare alcohol disposition capacities between different (ethnic) populations and as a tool to compare their different CNS-responses to multiple stable alcohol levels. We also investigated whether the clamping method could be useful as a future benchmarking entity in CNS-research, based on its fMRI effects on the brain at rest and its efficacy on tremor symptoms. Finally, we employed the method in an interaction study with a compound that is in development for addictive disorders including alcoholism. This thesis has examined several examples of situations where the alcohol clamp has been a useful research instrument during alcohol research and in early drug development

A comparison of the central nervous system effects of alcohol at pseudo-steady state in Caucasian and expatriate Japanese healthy male volunteers

Anesthesiolog

Pharmacokinetics and central nervous system effects of the novel dopamine D-3 receptor antagonist GSK598809 and intravenous alcohol infusion at pseudo-steady state

Neurological Motor Disorder

The effects of TPA023, a GABA(A)alpha(2,3) subtype-selective partial agonist, on essential tremor in comparison to alcohol

Stress-related psychiatric disorders across the life spa

Pseudocontinuous arterial spin labeling reveals dissociable effects of morphine and alcohol on regional cerebral blood flow

We have examined sensitivity and specificity of pseudocontinuous arterial spin labeling (PCASL) to detect global and regional changes in cerebral blood flow (CBF) in response to two different psychoactive drugs. We tested alcohol and morphine in a placebo-controlled, double-blind randomized study in 12 healthy young men. Drugs were administered intravenously. Validated pharmacokinetic protocols achieved minimal intersubject and intrasubject variance in plasma drug concentration. Permutation-based statistical testing of a mixed effect repeated measures model revealed a widespread increase in absolute CBF because of both morphine and alcohol. Conjunction analysis revealed overlapping effects of morphine and alcohol on absolute CBF in the left anterior cingulate, right hippocampus, right insula, and left primary sensorimotor areas. Effects of morphine and alcohol on relative CBF (obtained from z-normalization of absolute CBF maps) were significantly different in the left putamen, left frontoparietal network, cerebellum, and the brainstem. Corroborating previous PET results, our findings suggest that PCASL is a promising tool for central nervous system drug research. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 1321-1333; doi:10.1038/jcbfm.2010.234; published online 19 January 2011Perioperative Medicine: Efficacy, Safety and Outcom

Combining Hepatic Percutaneous Perfusion with Ipilimumab plus Nivolumab in advanced uveal melanoma (CHOPIN): study protocol for a phase Ib/randomized phase II trial

Background: While immune checkpoint inhibition (ICI) has revolutionized the treatment of metastatic cutaneous melanoma, no standard treatments are available for patients with metastatic uveal melanoma (UM). Several locoregional therapies are effective in the treatment of liver metastases, such as percutaneous hepatic perfusion with melphalan (M-PHP). The available literature suggests that treatment with ICI following locoregional treatment of liver UM metastases can result in clinical response. We hypothesize that combining M-PHP with ICI will lead to enhanced antigen presentation and increased immunomodulatory effect, improving control of both hepatic and extrahepatic disease.Methods: Open-label, single-center, phase Ib/randomized phase II trial, evaluating the safety and efficacy of the combination of M-PHP with ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-1 antibody) in patients with unresectable hepatic metastases of UM in first-line treatment, with or without the limited extrahepatic disease. The primary objective is to determine the safety, toxicity, and efficacy of the combination regimen, defined by maximum tolerated dose (MTD) and progression-free survival (PFS) at 1 year. Secondary objectives include overall survival (OS) and overall response rate (ORR). A maximum of 88 patients will be treated in phase I and phase II combined. Baseline characteristics will be described with descriptive statistics (t-test, chi-square test). To study the association between risk factors and toxicity, a logistic regression model will be applied. PFS and OS will be summarized using Kaplan-Meier curves.Discussion: This is the first trial to evaluate this treatment combination by establishing the maximum tolerated dose and evaluating the efficacy of the combination treatment. M-PHP has shown to be a safe and effective treatment for UM patients with liver metastases and became the standard treatment option in our center. The combination of ICI with M-PHP is investigated in the currently described trial which might lead to a better treatment response both in and outside the liver.Experimentele farmacotherapi

Combining Hepatic Percutaneous Perfusion with Ipilimumab plus Nivolumab in advanced uveal melanoma (CHOPIN): study protocol for a phase Ib/randomized phase II trial

Background: While immune checkpoint inhibition (ICI) has revolutionized the treatment of metastatic cutaneous melanoma, no standard treatments are available for patients with metastatic uveal melanoma (UM). Several locoregional therapies are effective in the treatment of liver metastases, such as percutaneous hepatic perfusion with melphalan (M-PHP). The available literature suggests that treatment with ICI following locoregional treatment of liver UM metastases can result in clinical response. We hypothesize that combining M-PHP with ICI will lead to enhanced antigen presentation and increased immunomodulatory effect, improving control of both hepatic and extrahepatic disease.Methods: Open-label, single-center, phase Ib/randomized phase II trial, evaluating the safety and efficacy of the combination of M-PHP with ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-1 antibody) in patients with unresectable hepatic metastases of UM in first-line treatment, with or without the limited extrahepatic disease. The primary objective is to determine the safety, toxicity, and efficacy of the combination regimen, defined by maximum tolerated dose (MTD) and progression-free survival (PFS) at 1 year. Secondary objectives include overall survival (OS) and overall response rate (ORR). A maximum of 88 patients will be treated in phase I and phase II combined. Baseline characteristics will be described with descriptive statistics (t-test, chi-square test). To study the association between risk factors and toxicity, a logistic regression model will be applied. PFS and OS will be summarized using Kaplan-Meier curves.Discussion: This is the first trial to evaluate this treatment combination by establishing the maximum tolerated dose and evaluating the efficacy of the combination treatment. M-PHP has shown to be a safe and effective treatment for UM patients with liver metastases and became the standard treatment option in our center. The combination of ICI with M-PHP is investigated in the currently described trial which might lead to a better treatment response both in and outside the liver