The Maximum Tolerated Dose and Secondary Mechanisms of Carcinogenesis

2021 ◽  
pp. 125-144
Author(s):  
James S. MacDonald ◽  
Harvey E. Scribner
Keyword(s):  
Maximum Tolerated Dose ◽  
Mechanisms Of Carcinogenesis

Device therapy of resistant hypertension

2013 ◽  
Vol 154 (6) ◽  
pp. 203-208 ◽  
Author(s):  
Gábor Simonyi ◽  
J. Róbert Bedros ◽  
Mihály Medvegy
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Risk ◽  
Resistant Hypertension ◽  
Carotid Sinus ◽  
Maximum Tolerated Dose ◽  
Reduce Blood Pressure ◽  
Nerve Fibers ◽  
Uncontrolled Hypertension ◽  
Sympathetic Nerve Fibers ◽  
Treatment Of Hypertension

It is well known that hypertension is an independent cardiovascular risk factor. Treatment of hypertension frequently includes administration of three or more drugs. Resistant hypertension is defined when blood pressure remains above target value despite full doses (the patient’s maximum tolerated dose) of antihypertensive medication consisting of at least three different classes of drugs including a diuretic. Pharmacological treatment of hypertension is often unsuccessful despite the increasing number of drug combinations. Uncontrolled hypertension, however, increases the cardiovascular risk. Device treatment of resistant hypertension is currently testing two major fields. One of them the stimulation of baroreceptors in the carotid sinus and the other is radiofrequency ablation of sympathetic nerve fibers around renal arteries to reduce blood pressure in drug resistant hypertension. Orv. Hetil., 2013, 154, 203–208.

PCSK9 Inhibitors: Novel Therapeutic Strategies for Lowering LDLCholesterol

2018 ◽  
Vol 19 (2) ◽  
pp. 165-176 ◽  
Author(s):  
Yan Wang ◽  
Zhao-Peng Liu
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Maximum Tolerated Dose ◽  
Therapeutic Strategies ◽  
Low Density ◽  
Pcsk9 Inhibitors ◽  
Cvd Risk ◽  
Safety Issues ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Statins are currently the major therapeutic strategies to lower low-density lipoprotein cholesterol (LDL-C) levels. However, a number of hypercholesterolemia patients still have a residual cardiovascular disease (CVD) risk despite taking the maximum-tolerated dose of statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein receptor (LDLR), inducing its degradation in the lysosome and inhibiting LDLR recirculating to the cell membranes. The gain-offunction mutations in PCSK9 elevate the LDL-C levels in plasma. Therefore, PCSK9 inhibitors become novel therapeutic approaches in the treatment of hypercholesterolemia. Several PCSK9 inhibitors have been under investigation, and much progress has been made in clinical trials, especially for monoclonal antibodies (MoAbs). Two MoAbs, evolocumab and alirocumab, are now in clinical use. In this review, we summarize the development of PCSK9 inhibitors, including antisense oligonucleotides (ASOs), small interfering RNA (siRNA), small molecule inhibitor, MoAbs, mimetic peptides and adnectins, and the related safety issues.

A Phase I Study of OMN54 (Aneustat™) in Patients with Advanced Malignancies

2020 ◽  
Vol 7 (2) ◽  
pp. 125-132
Author(s):  
Karen A. Gelmon ◽  
Christian Kollmannsberger ◽  
Stephen Chia ◽  
Anna V. Tinker ◽  
Teresa Mitchell ◽  
...  
Keyword(s):  
Phase I ◽  
Salvia Miltiorrhiza ◽  
Performance Status ◽  
Parent Drug ◽  
Maximum Tolerated Dose ◽  
Ecog Performance Status ◽  
Advanced Malignancies ◽  
Gi Toxicity ◽  
Adequate Organ Function ◽  
Recommended Phase Ii Dose

Background/Objective: With the increasing interest in natural products, a phase I openlabel study of OMN54 (Aneustat™) in patients with advanced malignancies was initiated to determine toxicity, maximum tolerated dose (MTD), dose limiting toxicities (DLT), and pharmacokinetics (PK). OMN54 is a multitargeted agent, combining three Chinese botanicals; Ganoderma lucidium, Salvia miltiorrhiza and Scutellaria barbata. Methods: Eligible patients (pts) were >18 years of age with advanced solid tumors, able to swallow oral capsules, ECOG performance status < 2, measurable disease as defined by RECIST 1.1 and adequate organ function. Results: Twenty-two patients were enrolled in 6 dose levels, 2 with daily dosing and 4 with twicedaily dosing ranging from 1 to 5 grams daily. All were evaluated for toxicity and 20 for response. No treatment-related dose-limiting toxicities (DLTs) were reported and the recommended phase II dose (RP2D) was determined to be 2.5 g twice daily. Seven adverse events in 5 patients were reported as possibly drug-related; 6 were GI toxicity and 1 was a skin disorder. All were grade 1 except one grade 2 vomiting. No RECIST responses were seen. Six pts were treated with > 2 cycles; one for 8 cycles. Four patients had reductions in TGF –β and EGF, exploratory biomarkers possibly suggestive of a drug effect. Plasma half-lives of 1 -2 hours were noted for all parent drug chemical markers with no accumulation over time. Conclusion: OMN54 was well tolerated, with no DLTs observed. Further studies at the RP2D will assess the biological activity.

All-trans retinoic acid: tolerance and biologic effects in myelodysplastic syndrome.

1993 ◽  
Vol 11 (8) ◽  
pp. 1489-1495 ◽  
Author(s):  
R Kurzrock ◽  
E Estey ◽  
M Talpaz
Keyword(s):  
Retinoic Acid ◽  
Side Effects ◽  
Myelodysplastic Syndrome ◽  
Acid Tolerance ◽  
Maximum Tolerated Dose ◽  
Significant Activity ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Biologic Effects ◽  
Dose Levels

PURPOSE We conducted a study to evaluate the tolerance to and biologic effects of all-trans retinoic acid in patients with myelodysplastic syndrome. PATIENTS AND METHODS Thirty-nine patients with myelodysplastic syndrome were treated with oral all-trans retinoic acid for 6 weeks. Dose levels were 10, 25, 50, 100, 150, 200, and 250 mg/m2/d. At least three patients were treated on each dose level. RESULTS The most common side effects were mucocutaneous dryness and erythema, and hypertriglyceridemia. Dose-limiting side effects were diverse and included dermatitic problems, sensorineural hearing loss, headaches, nausea and vomiting, myalgias, and dyspnea. The maximum-tolerated dose was 150 mg/m2/d. Only one response was seen among 29 patients considered assessable for response. CONCLUSION All-trans retinoic acid can be safely administered to patients at doses up to 150 mg/m2/d for 6 weeks. However, as administered in this study, this compound does not appear to have significant activity in myelodysplastic syndromes.

scholarly journals A Phase Ib Clinical Trial of Metformin and Chloroquine in Patients with IDH1-Mutated Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2474
Author(s):  
Mohammed Khurshed ◽  
Remco J. Molenaar ◽  
Myra E. van Linde ◽  
Ron A. Mathôt ◽  
Eduard A. Struys ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Intrahepatic Cholangiocarcinoma ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Idh1 Mutation ◽  
Resonance Spectroscopy ◽  
Isocitrate Dehydrogenase 1 ◽  
Who Grade ◽  
Phase Ib

Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid IDH1-mutated tumors produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are more vulnerable to disruption of their metabolism. Methods: Patients with IDH1-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine. The primary objective was to determine the occurrence of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Radiological and biochemical tumor responses to metformin and chloroquine were investigated using CT/MRI scans and magnetic resonance spectroscopy (MRS) measurements of D-2HG levels in serum. Results: Seventeen patients received study treatment for a median duration of 43 days (range: 7–74 days). Of twelve evaluable patients, 10 patients discontinued study medication because of progressive disease and two patients due to toxicity. None of the patients experienced a DLT. The MTD was determined to be 1500 mg of metformin two times a day and 200 mg of chloroquine once a day. A serum D/L-2HG ratio of ≥4.5 predicted the presence of an IDH1 mutation with a sensitivity of 90% and a specificity of 100%. By utilization of digital droplet PCR on plasma samples, we were able to detect tumor-specific IDH1 hotspot mutations in circulating tumor DNA (ctDNA) in investigated patients. Conclusion: Treatment of advanced IDH1-mutated solid tumors with metformin and chloroquine was well tolerated but did not induce a clinical response in this phase Ib clinical trial.

scholarly journals A Bayesian dose-finding design for outcomes evaluated with uncertainty

2021 ◽  
pp. 174077452110015
Author(s):  
Matthew J Schipper ◽  
Ying Yuan ◽  
Jeremy MG Taylor ◽  
Randall K Ten Haken ◽  
Christina Tsien ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Data Augmentation ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Continual Reassessment Method ◽  
Number Of Patients ◽  
Continual Reassessment ◽  
Partially Observed ◽  
Dose Limiting Toxicity

Introduction: In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity. Methods: We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches. Results: Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose. Conclusion: Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

Multidimensional Phase I Dose Ranging Trials for Stroke Recovery Interventions: Key Challenges and How to Address Them

2021 ◽  
pp. 154596832110193
Author(s):  
Emily J. Dalton ◽  
Leonid Churilov ◽  
Natasha A. Lannin ◽  
Dale Corbett ◽  
Bruce C. V. Campbell ◽  
...  
Keyword(s):  
Decision Support ◽  
Phase I ◽  
Early Phase ◽  
Phase I Trial ◽  
Systematic Approach ◽  
Decision Support Tool ◽  
Maximum Tolerated Dose ◽  
Stroke Recovery ◽  
Support Tool ◽  
Dose Ranging

Despite an increase in the amount of published stroke recovery research, interventions have failed to markedly affect the trajectory of recovery poststroke. We argue that early-phase research to systematically investigate dose is an important contributor to advance the science underpinning stroke recovery. In this article, we aim to ( a) define the problem of insufficient use of a systematic approach to early-phase, multidimensional dose articulation research and ( b) propose a solution that applies this approach to design a multidimensional phase I trial to identify the maximum tolerated dose (MTD). We put forward a design template as a decision support tool to increase knowledge of how to develop a phase I dose-ranging trial for nonpharmaceutical stroke recovery interventions. This solution has the potential to advance the development of efficacious stroke recovery interventions, which include activity-based rehabilitation interventions.

Relationships between Cellular Toxicity, the Maximum Tolerated Dose, Lipophilicity and Electrophilicity

1992 ◽  
Vol 20 (4) ◽  
pp. 549-562
Author(s):  
Herbert S. Rosenkranz ◽  
Edwin J. Matthews ◽  
Gilles Klopman
Keyword(s):  
Cultured Cells ◽  
Chemical Properties ◽  
Maximum Tolerated Dose ◽  
Log P ◽  
Lumo Energy ◽  
Cellular Toxicity ◽  
Water Partition Coefficient ◽  
The Us ◽  
Lowest Unoccupied Molecular Orbital ◽  
Rats And Mice

Results on cellular toxicity and maximum tolerated dose (MTD) for rats and mice were available for approximately 175 chemicals tested by the US National Toxicology Program. Additionally, the computed log P (log octanol-water partition coefficient) and the lowest unoccupied molecular orbital (LUMO) energy values, a measure of electrophilicity were also available for most of these chemicals. Analysis of the chemicals on the basis of their physical and quantum chemical properties and their toxic effects on cultured cells and rodents showed that: 1) as a group, the more toxic chemicals showed a trend towards higher LUMO energies (i.e. less electrophilic); 2) cytotoxic chemicals exhibited increased lipophilicity; and 3) cytotoxic chemicals were associated with increased systemic toxicity (as measured by the MTD). None of these relationships was expressed in a significant linear fashion as a function of the concentration at which the chemicals exhibited cytotoxicity.

Sign in / Sign up

Export Citation Format

Share Document