Neuroleptic Plasma Concentrations and Clinical Response: In Search of a Therapeutic Window

1988 ◽  
Vol 22 (5) ◽  
pp. 373-380 ◽  
Author(s):  
John J. Sramek ◽  
Steven G. Potkin ◽  
Rhoda Hahn
Keyword(s):  
Side Effects ◽  
Clinical Response ◽  
Study Design ◽  
Therapeutic Response ◽  
Plasma Concentrations ◽  
Therapeutic Window ◽  
Fixed Dose ◽  
The Relationship

There is much interest in finding a therapeutic window for commonly used neuroleptics so that dosage can be individualized and side effects minimized. The authors review specific requirements of good study design and survey the literature that has investigated the relationship between therapeutic response and plasma concentrations of neuroleptics. The evidence from a number of fixed-dose haloperidol studies suggests, but does not yet prove, the existence of a therapeutic window for this compound.

scholarly journals NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Patrick J. Mansky ◽  
Dawn B. Wallerstedt ◽  
Timothy S. Sannes ◽  
Jamie Stagl ◽  
Laura Lee Johnson ◽  
...  
Keyword(s):  
Clinical Response ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Stage Iv ◽  
Dosage Level ◽  
Maximum Tolerated Dose ◽  
Stage I ◽  
Fixed Dose ◽  
Mistletoe Lectin ◽  
Mistletoe Extract

Purpose.European Mistletoe (Viscum albumL.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM.Methods.Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery.Results.DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380 mg/m2and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high.Conclusion.GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone.

scholarly journals Morphine and Clonidine Synergize to Ameliorate Low Back Pain in Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Maral Tajerian ◽  
Magali Millecamps ◽  
Laura S. Stone
Keyword(s):  
Low Back Pain ◽  
Back Pain ◽  
Side Effects ◽  
Adverse Reactions ◽  
Therapeutic Outcome ◽  
Therapeutic Window ◽  
Fixed Dose ◽  
Null Mouse ◽  
Low Back ◽  
Pharmacological Agents

Chronic low back pain (LBP) is a debilitating condition associated with signs of axial and radiating pain. In humans with chronic LBP, opioids are often prescribed with varying outcomes and a multitude of side effects. Combination therapies, in which multiple pharmacological agents synergize to ameliorate pain without similar potentiation of adverse reactions, may be useful in improving therapeutic outcome in these patients. The SPARC-null mouse model of low back pain due to disc degeneration was used to assess the effects of opioid (morphine) and α2-adrenergic agonist (clonidine) coadministration on measures of axial and radiating pain. The results indicate that systemic morphine and clonidine, coadministered at a fixed dose of 100 : 1 (morphine : clonidine), show a synergistic interaction in reversing signs of axial LBP, in addition to improving the therapeutic window for radiating LBP. Furthermore, these improvements were observed in the absence of synergy in assays of motor function which are indicative of side effects such as sedation and motor incoordination. These data show that the addition of low-dose systemic clonidine improves therapeutic outcome in measures of both axial and radiating pain. Combination therapy could be of enormous benefit to patients suffering from chronic LBP.

Pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate in advanced breast cancer patients.

1992 ◽  
Vol 10 (7) ◽  
pp. 1176-1182 ◽  
Author(s):  
M C Etienne ◽  
G Milano ◽  
M Frenay ◽  
N Renee ◽  
E Francois ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Advanced Breast Cancer ◽  
Medroxyprogesterone Acetate ◽  
Objective Response ◽  
Plasma Concentrations ◽  
Advanced Breast ◽  
Response To Treatment ◽  
Prolonged Treatment ◽  
Therapeutic Window

PURPOSE Medroxyprogesterone acetate (MPA) is one of the major drugs used in endocrine therapy for advanced breast cancer. However, its optimal dose still has not been clearly established. Response to treatment and drug-related side effects were analyzed as a function of plasma MPA concentrations during prolonged MPA treatment. PATIENTS AND METHODS MPA plasma concentrations were measured (high-performance liquid chromatography [HPLC] assay) at steady state (Css min) in 129 patients (mean age, 63 years; range, 34 to 87) treated by MPA (86% were treated orally exclusively with daily doses ranging from 400 to 2,000 mg). RESULTS A wide interpatient variability was noted in MPA Css min for the 70 patients who received 1,000 mg/d orally (median, 51 ng/mL; range, 10 to 269 ng/mL). Intrapatient analysis of the evolution of MPA Css min during prolonged treatment showed relative stability of MPA concentrations (mean CV, 20.6%). A weak but significant correlation was demonstrated between oral doses and MPA Css min (P = .016). Thirty-five percent of patients (45 of 129) developed MPA-related side effects that were associated with the highest plasma MPA concentrations; medians were 81 and 32 ng/mL for toxic and nontoxic treatments, respectively (P less than .001). Objective response was assessable in 55 patients who were treated by MPA exclusively. Plasma MPA concentrations were significantly different (P = .025) between patients with progressive disease (PD) (median, 46 ng/mL) and those with complete response (CR), partial response (PR), or stable disease (SD) (median 65 ng/mL). Comparison of CR plus PR versus SD versus PD showed only a tendency toward significant differences in MPA Css min (P = .07). Analysis of toxicity and response as a function of the oral dose did not show any significant relationship. These data suggested an optimal therapeutic window for MPA Css min located within 50 to 70 ng/mL. CONCLUSION This study demonstrates that plasma MPA concentration, as opposed to the administered dose, is a determining factor for toxicity and response therapy [corrected].

Plasma Concentrations of Protriptyline and Clinical Effects in Depressed Women

1976 ◽  
Vol 128 (4) ◽  
pp. 384-390 ◽  
Author(s):  
S. F. Whyte ◽  
A. J. Macdonald ◽  
G. J. Naylor ◽  
J. P. Moody
Keyword(s):  
Side Effects ◽  
Plasma Levels ◽  
Side Effect ◽  
Plasma Concentrations ◽  
Clinical Effects ◽  
Drug Plasma ◽  
Pre Treatment ◽  
Positive Correlations ◽  
Drug Plasma Levels ◽  
The Relationship

SummaryWe studied the relationship between side effects, clinical outcome and the drug plasma levels in 28 female depressed patients treated with protriptyline. After 3½ weeks treatment, patients with plasma levels within a median range (630 to 900 nmol/1) showed better responses to the drug than patients with plasma levels outside this range.There were no statistically significant correlations between plasma levels and side effect scores or ‘corrected’ side effect scores (scores after subtracting pre-treatment values) for the group at any time after starting the treatment. But we found positive correlations between plasma levels and ‘corrected’ side effect scores for the neurotic subgroup after 14 and 21 days of treatment. Other correlations between plasma levels and side effect scores were non-significant.

Clomipramine and Exposure for Compulsive Rituals: II. Plasma Levels, Side Effects and Outcome

1980 ◽  
Vol 136 (2) ◽  
pp. 161-166 ◽  
Author(s):  
R. S. Stern ◽  
I. M. Marks ◽  
D. Mawson ◽  
D. K. Luscombe
Keyword(s):  
Side Effects ◽  
Plasma Levels ◽  
Plasma Concentrations ◽  
Therapeutic Window ◽  
Obsessive Compulsive ◽  
Behavioural Treatment ◽  
Primary Metabolite ◽  
Exposure In Vivo

SummaryForty obsessive-compulsive ritualizers received nightly placebo or clomipramine up to 225 mgs nocte for 8 months, and received behavioural treatment (exposure in vivo) from weeks 4 to 10. Plasma concentrations of clomipramine and its primary metabolite N-desmethylclomipramine steadily increased over the first 4 weeks of treatment after which they remained relatively steady. Plasma levels correlated significantly with dose and with outcome but not with side effects. Patients with plasma clomipramine levels in the range 100–250 ng/ml and N-desmethylclomipramine levels between 230–550 ng/ml were found to improve significantly more than patients outside these ranges, thus suggesting a therapeutic window for clomipramine and its primary metabolite.

scholarly journals Impact on Antibiotic Resistance, Therapeutic Success, and Control of Side Effects in Therapeutic Drug Monitoring (TDM) of Daptomycin: A Scoping Review

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 263
Author(s):  
Carolina Osorio ◽  
Laura Garzón ◽  
Diego Jaimes ◽  
Edwin Silva ◽  
Rosa-Helena Bustos
Keyword(s):  
Side Effects ◽  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Bacterial Resistance ◽  
Plasma Concentrations ◽  
Resistant Bacteria ◽  
Therapeutic Drug ◽  
Therapeutic Success ◽  
Favorable Clinical Outcome ◽  
And Control

Antimicrobial resistance (AR) is a problem that threatens the search for adequate safe and effective antibiotic therapy against multi-resistant bacteria like methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococci (VRE) and Clostridium difficile, among others. Daptomycin is the treatment of choice for some infections caused by Gram-positive bacteria, indicated most of the time in patients with special clinical conditions where its high pharmacokinetic variability (PK) does not allow adequate plasma concentrations to be reached. The objective of this review is to describe the data available about the type of therapeutic drug monitoring (TDM) method used and described so far in hospitalized patients with daptomycin and to describe its impact on therapeutic success, suppression of bacterial resistance, and control of side effects. The need to create worldwide strategies for the appropriate use of antibiotics is clear, and one of these is the performance of therapeutic drug monitoring (TDM). TDM helps to achieve a dose adjustment and obtain a favorable clinical outcome for patients by measuring plasma concentrations of an administered drug, making a rational interpretation guided by a predefined concentration range, and, thus, adjusting dosages individually.

scholarly journals Foslevodopa/Foscarbidopa Is Well Tolerated and Maintains Stable Levodopa and Carbidopa Exposure Following Subcutaneous Infusion

2021 ◽  
pp. 1-8
Author(s):  
Matthew Rosebraugh ◽  
Wei Liu ◽  
Melina Neenan ◽  
Maurizio F. Facheris
Keyword(s):  
Steady State ◽  
Phase 1 ◽  
The United States ◽  
Therapeutic Window ◽  
Fixed Dose ◽  
Advanced Parkinson’S Disease ◽  
Subcutaneous Infusion ◽  
Study Results ◽  
Wide Range ◽  
Favorable Safety

Background: Foslevodopa/foscarbidopa, formerly known as ABBV-951, is a formulation of levodopa/carbidopa prodrugs with solubility that allows for subcutaneous (SC) infusion and is in development for the treatment of motor complications for patients with advanced Parkinson’s disease (aPD). Objective: The current work characterizes the levodopa (LD) and carbidopa (CD) pharmacokinetics (PK) following SC infusions of foslevodopa/foscarbidopa delivered at four different infusion rates in PD patients. Methods: This was a Phase 1, single ascending dose, single-blind study conducted in 28 adult male and female subjects at seven sites in the United States. Foslevodopa/foscarbidopa was administered via abdominal SC infusion in PD patients over 72 hours. Patients were stratified in 4 groups and received a fixed dose of foslevodopa/foscarbidopa based on their oral daily LD intake. Serial plasma PK samples were collected to assay for LD and CD concentrations. Safety and tolerability were assessed throughout the study. Results: LD exposure quickly reached steady state and remained stable with minimal fluctuations. Foslevodopa/foscarbidopa infusion provides stable LD and CD exposures compared to oral LD/CD dosing with the average steady-state exposure ranging from 747-4660 ng/mL for the different groups. Conclusion: Foslevodopa/foscarbidopa was able to provide stable LD and CD exposures in PD patients over 72 hours via SC route of delivery with very low fluctuation in LD concentration level across a wide range of clinically relevant exposures. Foslevodopa/foscarbidopa had a favorable safety profile. The low PK fluctuation following foslevodopa/foscarbidopa infusion is expected to maintain LD exposure to treat aPD patients within a narrow therapeutic window.

scholarly journals Neurological Complications of Biological Treatment of Psoriasis

Life ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 118
Author(s):  
Mateusz Kamil Ożóg ◽  
Beniamin Oskar Grabarek ◽  
Magdalena Wierzbik-Strońska ◽  
Magdalena Świder
Keyword(s):  
Nervous System ◽  
Side Effects ◽  
Biological Treatment ◽  
Biological Therapy ◽  
Neurological Complications ◽  
Tnf Alpha ◽  
Biological Drugs ◽  
Discontinuation Of Treatment ◽  
The Relationship ◽  
Alpha Therapy

In the available literature, little attention has been paid to the assessment of psoriasis and the biological therapy used for it and the nervous system. The purpose of this article is to discuss the relationship between psoriasis and the nervous system as well as to analyze the mechanisms that lead to neurological complications during anticytokine therapies in psoriasis. However, this connection requires further analysis. The use of biological drugs in psoriasis, although it yields positive therapeutic results, is not without numerous side effects. Serious neurological side effects of the therapy are most often visible with the use of anti-TNF-alpha, which is why patients should be monitored for their potential occurrence. Early detection of complications and rapid discontinuation of treatment with the drug may potentially increase the patient’s chances of a full recovery or improvement of his/her neurological condition. It also seems reasonable that, in the case of complications occurring during anti-TNF-alpha therapy, some of the drugs from other groups should be included in the therapy.

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