Therapeutic Window

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Benjamin Maasoumy - One of the best experts on this subject based on the ideXlab platform.

  • Systemic arterial blood pressure determines the Therapeutic Window of non-selective beta blockers in decompensated cirrhosis.
    Alimentary pharmacology & therapeutics, 2019
    Co-Authors: Tammo L. Tergast, Markus Kimmann, Hans Laser, Svetlana Gerbel, Michael P. Manns, Markus Cornberg, Benjamin Maasoumy
    Abstract:

    BACKGROUND The safety of non-selective β-blockers in patients with advanced cirrhosis has been questioned in recent years. It was hypothesised that there is a particular Therapeutic Window. However, the specific limits still need to be determined. AIM To evaluate potential limits of the Therapeutic Window of non-selective β-blocker therapy in patients with cirrhosis and ascites METHODS: The impact of non-selective β-blockers on 28-day transplant-free survival was analysed in a cohort of 624 consecutive patients with decompensated cirrhosis and ascites. Three potential limits were investigated: spontaneous bacterial peritonitis, acute-on-chronic liver failure, mean arterial blood pressure ≤ 82 and 

  • systemic arterial blood pressure determines the Therapeutic Window of non selective beta blockers in decompensated cirrhosis
    Alimentary Pharmacology & Therapeutics, 2019
    Co-Authors: Tammo L. Tergast, Markus Kimmann, Hans Laser, Svetlana Gerbel, Michael P. Manns, Markus Cornberg, Benjamin Maasoumy
    Abstract:

    BACKGROUND The safety of non-selective β-blockers in patients with advanced cirrhosis has been questioned in recent years. It was hypothesised that there is a particular Therapeutic Window. However, the specific limits still need to be determined. AIM To evaluate potential limits of the Therapeutic Window of non-selective β-blocker therapy in patients with cirrhosis and ascites METHODS: The impact of non-selective β-blockers on 28-day transplant-free survival was analysed in a cohort of 624 consecutive patients with decompensated cirrhosis and ascites. Three potential limits were investigated: spontaneous bacterial peritonitis, acute-on-chronic liver failure, mean arterial blood pressure ≤ 82 and < 65 mm Hg. RESULTS Treatment with non-selective β-blockers was associated with a higher 28-day transplant-free survival in the overall cohort (hazard ratio: 0.621; P = .035) as well as in patients with acute-on-chronic liver failure (hazard ratio: 0.578; P = .031) and those with spontaneous bacterial peritonitis (hazard ratio: 0.594; P = .073). In contrast, survival benefits were markedly attenuated in patients with a mean arterial blood pressure ≤ 82 mm Hg and completely lost in those with mean arterial blood pressure < 65 mm Hg (P = .536). In spontaneous bacterial peritonitis patients with a mean arterial blood pressure < 65 mm Hg non-selective β-blocker treatment was associated with renal impairment. Of note, among those with a mean arterial blood pressure ≥ 65 mm Hg non-selective β-blocker intake was consistently associated with superior transplant-free survival (hazard ratio: 0.582; P = .029) irrespective of the presence of spontaneous bacterial peritonitis (hazard ratio: 0.435; P = .028) or acute-on-chronic liver failure (hazard ratio: 0.480 P = .034). CONCLUSIONS Ascites, acute-on-chronic liver failure and spontaneous bacterial peritonitis do not limit the safe use of non-selective β-blockers in patients with cirrhosis. Mean arterial blood pressure might represent a better indicator to determine the Therapeutic Window of non-selective β-blocker treatment.

Roman Kischel - One of the best experts on this subject based on the ideXlab platform.

  • Therapeutic Window of MuS110, a Single-Chain Antibody Construct Bispecific for Murine EpCAM and Murine CD3
    Cancer research, 2008
    Co-Authors: Maria Amann, Klaus Brischwein, Petra Lutterbuese, Grit Lorenczewski, Eva Krinner, Larissa Parr, Laetitia Petersen, Sandra Bruckmeier, Sandra Lippold, Roman Kischel
    Abstract:

    EpCAM (CD326) is one of the most frequently and highly expressed tumor-associated antigens known and recently has also been found on cancer stem cells derived from human breast, colon, prostate, and pancreas tumors. However, like many other tumor-associated antigens used for antibody-based immunoTherapeutic approaches, EpCAM is expressed on normal tissues including epithelia of pancreas, colon, lung, bile ducts, and breast. To assess the Therapeutic Window of an EpCAM/CD3-bispecific single-chain antibody construct of the bispecific T-cell engager (BiTE) class, we constructed murine surrogate of MT110 (muS110) from single-chain antibodies specific for murine EpCAM and CD3 antigens. Immunhistochemical analysis showed that, with minor differences, the expression of EpCAM protein on a large variety of tissues from man and mouse was similar with respect to distribution and level. MuS110 exhibited significant antitumor activity at as low as 5 microg/kg in both syngeneic 4T1 orthotopic breast cancer and CT-26 lung cancer mouse models. Dosing of muS110 for several weeks up to 400 microg/kg by intraanimal dose escalation was still tolerated, indicating existence of a significant Therapeutic Window for an EpCAM-specific BiTE antibody in mice. MuS110 was found to have similar in vitro characteristics and in vivo antitumor activity as MT110, a human EpCAM/human CD3-bispecific BiTE antibody that currently is in formal preclinical development.

  • Therapeutic Window of MuS110, a single-chain antibody construct bispecific for EpCAM (CD326) and CD3
    Molecular Cancer Therapeutics, 2007
    Co-Authors: Patrick A. Baeuerle, Maria Amann, Klaus Brischwein, Petra Lutterbuese, Grit Lorenczewski, Eva Krinner, Roman Kischel, Ralf Lutterbuese, Peter Kufer, Bernd Schlereth
    Abstract:

    C270 EpCAM (CD326) is a well studied tumor-associated antigen that is frequently expressed at high levels on a variety of human adeno and squamous cell carcinoma. Recently, EpCAM has also been found expressed on cancer stem cells from breast, colon, prostate and pancreas tumors. However, like many other tumor-associated antigens used for antibody-based immunoTherapeutic approaches, EpCAM is also present on normal tissues including epithelia of pancreas, colon, lung, bile ducts and breast. Sequestration of EpCAM epitopes by associated membrane proteins and within intercellular boundaries of normal epithelia, and its overexpression on some tumors relative to normal tissue may explain the benign safety profile of some but not all EpCAM-directed antibody-based therapies.
 MT110 is an EpCAM-/CD3-bispecific single-chain antibody construct with high potency against EpCAM-positive human carcinoma lines. In vivo, eradication in immunodeficient mice of established tumors from human cell lines and of authentic tumor tissue of patients by low µg-doses of MT110 has been reported. Because MT110 is specific for human EpCAM and human CD3, we sought to assess the safety and Therapeutic Window of this class of bispecific antibodies with a biosimilar molecule. To this end, muS110 (for murine surrogate of MT110) was constructed from the variable domains of two monoclonal antibodies with specificity for mouse EpCAM and mouse CD3. In in-vitro assays, muS110 showed similar bioactivity with murine cells as MT110 with human cells. Immunhistochemical analysis revealed that, with some differences, the expression of EpCAM on a large variety of tissues from man and mouse was comparable with respect to tropism and intensity.
 MuS110 exhibited highly significant anti-tumor activity in both syngeneic 4T1 orthotopic breast cancer and CT26 lung cancer mouse models. Administration of muS110 for several weeks at doses exceeding by far the efficacious dose levels was well tolerated, indicating existence of a significant Therapeutic Window for the EpCAM-specific BiTE molecule. The dose-limiting toxicity of muS110 was related to cytokine release but not to damage of EpCAM-expressing normal tissues. These data show that EpCAM-specific BiTE molecules can distinguish EpCAM expressed on tumor cells from the EpCAM expressed on normal tissue, suggesting that a Therapeutic Window may also exist for the human-specific BiTE MT110, which is in formal preclinical development for the treatment of patients with EpCAM-expressing adenocarcinoma.

Stefan Jun Groiss - One of the best experts on this subject based on the ideXlab platform.

  • Directional Deep Brain Stimulation of the Thalamic Ventral Intermediate Area for Essential Tremor Increases Therapeutic Window.
    Neuromodulation : journal of the International Neuromodulation Society, 2020
    Co-Authors: Sabine Bruno, Petyo Nikolov, Christian J. Hartmann, Carlos Trenado, Philipp J. Slotty, Jan Vesper, Alfons Schnitzler, Stefan Jun Groiss
    Abstract:

    Objectives Deep brain stimulation (DBS) of the posterior subthalamic area (PSA) and the ventral intermediate thalamic nucleus (VIM) is a well-established therapy for essential tremor (ET), but it is frequently associated with side effects like dysarthria or gait ataxia. Directional DBS (dDBS) may be a way to activate fiber tracts more selectively. Is dDBS for ET superior to omnidirectional DBS (oDBS) regarding Therapeutic Window and clinically as effective as oDBS? Materials and methods Ten patients with ET treated with PSA/VIM-DBS were recruited. Therapeutic Window served as primary outcome parameter; clinical efficacy, volume of neuronal activation, and total electrical energy delivered (TEED) served as secondary outcome parameters. Therapeutic Window was calculated for all three dDBS directions and for oDBS by determining Therapeutic thresholds and side effect thresholds. Clinical efficacy was assessed by comparing the effect of best dDBS and oDBS on tremor and ataxia rating scales, and accelerometry. Volume of neural activation and TEED were also calculated for both paradigms. Results For best dDBS, Therapeutic Window was wider and Therapeutic threshold was lower compared to oDBS. While side effect threshold did not differ, volume of neural activation was larger for dDBS. In terms of clinical efficacy, dDBS was as effective as oDBS. Conclusions dDBS for ET widens Therapeutic Window due to reduction of Therapeutic threshold. Larger volume of neural activation for dDBS at side effect threshold supports the notion of persistent directionality even at higher intensities. dDBS may compensate for slightly misplaced leads and should be considered first line for PSA/VIM-DBS.

  • Asleep Surgery May Improve the Therapeutic Window for Deep Brain Stimulation of the Subthalamic Nucleus
    Neuromodulation : journal of the International Neuromodulation Society, 2020
    Co-Authors: Farhad Senemmar, Christian J. Hartmann, Philipp J. Slotty, Jan Vesper, Alfons Schnitzler, Stefan Jun Groiss
    Abstract:

    Objective The effect of anesthesia type in terms of asleep vs. awake deep brain stimulation (DBS) surgery on Therapeutic Window (TW) has not been investigated so far. The objective of the study was to investigate whether asleep DBS surgery of the subthalamic nucleus (STN) improves TW for both directional (dDBS) and omnidirectional (oDBS) stimulation in a large single-center population. Materials and methods A total of 104 consecutive patients with Parkinson's disease (PD) undergoing STN-DBS surgery (80 asleep and 24 awake) were compared regarding TW, Therapeutic threshold, side effect threshold, improvement of Unified PD Rating Scale motor score (UPDRS-III) and degree of levodopa equivalent daily dose (LEDD) reduction. Results Asleep DBS surgery led to significantly wider TW compared to awake surgery for both dDBS and oDBS. However, dDBS further increased TW compared to oDBS in the asleep group only and not in the awake group. Clinical efficacy in terms of UPDRS-III improvement and LEDD reduction did not differ between groups. Conclusions Our study provides first evidence for improvement of Therapeutic Window by asleep surgery compared to awake surgery, which can be strengthened further by dDBS. These results support the notion of preferring asleep over awake surgery but needs to be confirmed by prospective trials.

  • Less is more - Pulse width dependent Therapeutic Window in deep brain stimulation for essential tremor.
    Brain stimulation, 2018
    Co-Authors: Alexia-sabine Moldovan, Christian J. Hartmann, Carlos Trenado, Philipp J. Slotty, Jan Vesper, Alfons Schnitzler, Nicola Meumertzheim, Stefan Jun Groiss
    Abstract:

    Abstract Background Shorter pulse widths than conventional pulse width settings may lead to reduction of side effects and therefore be a valuable Therapeutic option for deep brain stimulation (DBS) in patients with essential tremor (ET). Objective To compare the DBS effect of shorter pulse width at 40 μs (DBS-40 μs) to conventional pulse width at 60 μs (DBS-60 μs) on the Therapeutic Window in ET patients. Methods For this prospective, randomized, double-blind, crossover study 9 ET patients with chronic DBS of the ventral intermediate nucleus (VIM)/posterior subthalamic area (PSA) were recruited. Therapeutic Window was calculated by determining efficacy and side effect thresholds for DBS-40 μs and DBS-60 μs. Tremor Rating Scales and Kinesia tremor analyses were used to compare clinical efficacy between the considered settings and deactivated DBS (DBS-OFF). Volume of neural activation (VNA) was calculated for both efficacy and side effect thresholds at each pulse width. Results DBS-40 μs showed a significantly larger Therapeutic Window than DBS-60 μs mainly due to higher side-effect thresholds. Both conditions significantly improved tremor compared to DBS-OFF, while efficacy was comparable between DBS-40 μs and DBS-60 μs. Moreover, VNA at efficacy threshold was smaller and less energy was required for tremor suppression with DBS-40 μs compared to DBS-60 μs. Conclusions VIM/PSA-DBS with short pulse width represents a promising programming option for DBS in ET as it reduces side effects while maintaining efficient tremor suppression. Furthermore, our data support the notion of pulse width dependent selective modulation of distinct fiber tracts leading to widening of the Therapeutic Window.

Justin A. Zivin - One of the best experts on this subject based on the ideXlab platform.

  • Factors determining the Therapeutic Window for stroke
    Neurology, 1998
    Co-Authors: Justin A. Zivin
    Abstract:

    The duration of the Window to treat acute cerebral ischemia has become an important question since the first effective drug for stroke victims has become available. Statistical analysis of relevant animal studies suggests that irreversible focal injury begins within a few minutes and is complete within about 6 hours. There will be substantial difficulties in attempting to obtain accurate estimates of the duration of ischemia that causes permanent damage in patients unless technical obstacles are overcome. Empirical estimates of the Therapeutic Window for stroke can be obtained from properly designed clinical trials, but optimal care will continue to necessitate urgent treatment.

Jari Koistinaho - One of the best experts on this subject based on the ideXlab platform.

  • a tetracycline derivative minocycline reduces inflammation and protects against focal cerebral ischemia with a wide Therapeutic Window
    Proceedings of the National Academy of Sciences of the United States of America, 1999
    Co-Authors: Juha Yrjanheikki, Tiina Tikka, Riitta Keinanen, Gundars Goldsteins, Pak H Chan, Jari Koistinaho
    Abstract:

    The only treatment of patients with acute ischemic stroke is thrombolytic therapy, which benefits only a fraction of stroke patients. Both human and experimental studies indicate that ischemic stroke involves secondary inflammation that significantly contributes to the outcome after ischemic insult. Minocycline is a semisynthetic second-generation tetracycline that exerts antiinflammatory effects that are completely separate from its antimicrobial action. Because tetracycline treatment is clinically well tolerated, we investigated whether minocycline protects against focal brain ischemia with a wide Therapeutic Window. Using a rat model of transient middle cerebral artery occlusion, we show that daily treatment with minocycline reduces cortical infarction volume by 76 ± 22% when the treatment is started 12 h before ischemia and by 63 ± 35% when started even 4 h after the onset of ischemia. The treatment inhibits morphological activation of microglia in the area adjacent to the infarction, inhibits induction of IL-1β-converting enzyme, and reduces cyclooxygenase-2 expression and prostaglandin E2 production. Minocycline had no effect on astrogliosis or spreading depression, a wave of ionic transients thought to contribute to enlargement of cortical infarction. Treatment with minocycline may act directly on brain cells, because cultured primary neurons were also salvaged from glutamate toxicity. Minocycline may represent a prototype of an antiinflammatory compound that provides protection against ischemic stroke and has a clinically relevant Therapeutic Window.

  • a tetracycline derivative minocycline reduces inflammation and protects against focal cerebral ischemia with a wide Therapeutic Window
    Proceedings of the National Academy of Sciences of the United States of America, 1999
    Co-Authors: Juha Yrjanheikki, Tiina Tikka, Riitta Keinanen, Gundars Goldsteins, Pak H Chan, Jari Koistinaho
    Abstract:

    The only treatment of patients with acute ischemic stroke is thrombolytic therapy, which benefits only a fraction of stroke patients. Both human and experimental studies indicate that ischemic stroke involves secondary inflammation that significantly contributes to the outcome after ischemic insult. Minocycline is a semisynthetic second-generation tetracycline that exerts antiinflammatory effects that are completely separate from its antimicrobial action. Because tetracycline treatment is clinically well tolerated, we investigated whether minocycline protects against focal brain ischemia with a wide Therapeutic Window. Using a rat model of transient middle cerebral artery occlusion, we show that daily treatment with minocycline reduces cortical infarction volume by 76 +/- 22% when the treatment is started 12 h before ischemia and by 63 +/- 35% when started even 4 h after the onset of ischemia. The treatment inhibits morphological activation of microglia in the area adjacent to the infarction, inhibits induction of IL-1beta-converting enzyme, and reduces cyclooxygenase-2 expression and prostaglandin E(2) production. Minocycline had no effect on astrogliosis or spreading depression, a wave of ionic transients thought to contribute to enlargement of cortical infarction. Treatment with minocycline may act directly on brain cells, because cultured primary neurons were also salvaged from glutamate toxicity. Minocycline may represent a prototype of an antiinflammatory compound that provides protection against ischemic stroke and has a clinically relevant Therapeutic Window.