Imipramine and Amitriptyline Plasma Concentrations and Clinical Response in Major Depression

1986 ◽  
Vol 148 (1) ◽  
pp. 52-57 ◽  
Author(s):  
James H. Kocsis ◽  
Israel Hanin ◽  
Charles Bowden ◽  
David Brunswick
Keyword(s):  
Clinical Response ◽  
Plasma Concentrations ◽  
Drug Level ◽  
Double Blind ◽  
Level Measurement ◽  
Monitoring Drug ◽  
Drug Concentrations ◽  
Curvilinear Relationships ◽  
Blood Drug Level ◽  
Demethylated Metabolites

Plasma drug concentrations and clinical response were measured in two groups of hospitalised depressed patients, who received amitriptyline or Imipramine double-blind, in a dosage of 250 mg for four weeks. Virtually no significant linear or curvilinear relationships were found between any plasma measure and any measure of clinical response. Modest but significant direct relationships were found between age and concentration of parent drugs but not demethylated metabolites. Blood drug level measurement therefore appears to be of little value in monitoring drug treatment of depressed in-patients.

Pseudoephedrine is without ergogenic effects during prolonged exercise

1996 ◽  
Vol 81 (6) ◽  
pp. 2611-2617 ◽  
Author(s):  
Hunter Gillies ◽  
Wayne E. Derman ◽  
Timothy D. Noakes ◽  
Peter Smith ◽  
Alicia Evans ◽  
...  
Keyword(s):  
Urinary Excretion ◽  
High Intensity ◽  
Muscle Function ◽  
Prolonged Exercise ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
High Intensity Exercise ◽  
Double Blind ◽  
Drug Concentrations ◽  
Ergogenic Effects

Gillies, Hunter, Wayne E. Derman, Timothy D. Noakes, Peter Smith, Alicia Evans, and Gary Gabriels.Pseudoephedrine is without ergogenic effects during prolonged exercise. J. Appl. Physiol. 81(6): 2611–2617, 1996.—This study was designed to measure whether a single dose of 120 mg pseudoephedrine ingested 120 min before exercise influences performance during 1 h of high-intensity exercise. The effects of exercise on urinary excretion of the drug were also studied. Ten healthy male cyclists were tested on two occasions, separated by at least 7 days, by using a randomly assigned, double-blind, placebo-controlled, crossover design. Exercise performance was tested during a 40-km trial on a laboratory cycle ergometer, and skeletal muscle function was measured during isometric contractions. On a third occasion, subjects ingested 120 mg pseudoephedrine but did not exercise [control (C)]. Pseudoephedrine did not influence either time trial performance [drug (D) vs. placebo: 58.1 ± 1.4 (SE) vs. 58.7 ± 1.5 min] or isometric muscle function. Urinary pseudoephedrine concentrations were significantly increased 1 h after exercise (D vs. C: 114.3 ± 27.2 vs. 35.4 ± 13.1 μg/ml; P < 0.05). Peak plasma pseudoephedrine concentrations ( P < 0.05) but not time taken to reach peak plasma concentrations or the area under the plasma pseudoephedrine concentration vs. time curve was significantly increased in the total group with exercise (D vs. C). In three subjects, plasma pseudoephedrine concentrations were not influenced by exercise. Only these subjects showed increased urinary pseudoephedrine excretion during exercise. We conclude that a single therapeutic dose of pseudoephedrine did not have a measurable ergogenic effect during high-intensity exercise of 1-h duration, but plasma drug concentrations and urinary excretion were altered by exercise. These findings have practical relevance to doping control regulations in international sporting competitions.

scholarly journals Plasma Drug Level Validates Self-Reported Adherence but Predicts Limited Specificity for Nonadherence to Antiretroviral Therapy

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Robert Balikuddembe ◽  
Joshua Kayiwa ◽  
David Musoke ◽  
Muhammad Ntale ◽  
Steven Baveewo ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Low Income ◽  
Plasma Levels ◽  
Plasma Concentrations ◽  
Drug Level ◽  
Low Income Countries ◽  
Plasma Drug ◽  
Cross Sectional ◽  
Drug Concentrations ◽  
Emergence Of Resistance

Introduction. Adherence to antiretroviral therapy (ART) in low-income countries is mainly assessed by self-reported adherence (S-RA) without drug level determination. Nonadherence is an important factor in the emergence of resistance to ART, presenting a need for drug level determination. Objective. We set out to establish the relationship between plasma stavudine levels and S-RA and validate S-RA against the actual plasma drug concentrations. Methods. A cross-sectional investigation involving 234 patients in Uganda. Stavudine plasma levels were determined using high-performance liquid chromatography. We compared categories of plasma levels of stavudine with S-RA using multivariable logistic regression models. Results. Overall, 194/234 patients had S-RA ≥ 95% (good adherence) and 166/234 had stavudine plasma concentrations ≥ 36 nmol/L (therapeuticconcentration). Patients with good S-RA were eight times more likely to have stavudine levels within therapeutic concentration (Adjusted Odds Ratio: 7.7, 95% Confidence Interval: 3.5–7.0). However, of the 194 patients with good S-RA, 21.7% had below therapeutic concentrations. S-RA had high sensitivity for adherence (91.6%), but limited specificity for intrinsic poor adherence (38.2%). Conclusions. S-RA is a good tool for assessing adherence, but has low specificity in detecting nonadherence, which has implications for emergence of resistance.

scholarly journals Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations

2020 ◽  
Author(s):  
Catia Marzolini ◽  
Felix Stader ◽  
Marcel Stoeckle ◽  
Fabian Franzeck ◽  
Adrian Egli ◽  
...  
Keyword(s):  
Treatment Initiation ◽  
Plasma Concentrations ◽  
Drug Level ◽  
Cytochrome P450 3A4 ◽  
Inflammation Marker ◽  
C Reactive Protein ◽  
Metabolizing Enzymes ◽  
Reactive Protein ◽  
Drug Concentrations ◽  
Study Participants

AbstractBackgroundCoronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the values of acute phase inflammation marker C-reactive protein (CRP).MethodsLPV plasma concentrations were prospectively collected in 92 patients hospitalized at our institution. Lopinavir/ritonavir was administered 12-hourly, 800/200 mg on day 1, and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24 and 48 hours. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination.ResultsThe median age of study participants was 59 (range 24–85) years, and 71% were male. The median duration from symptom onset to hospitalization and treatment initiation was 7 days (IQR 4–10) and 8 days (IQR 5–10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 μg/mL (IQR 18.9–31.5). LPV plasma concentrations positively correlated with CRP values (r=0.37, p<0.001), and were significantly lower when tocilizumab was preadministrated. No correlation was found between HCQ concentrations and CRP values.ConclusionsHigh LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 EC50 values indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.

scholarly journals Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Catia Marzolini ◽  
Felix Stader ◽  
Marcel Stoeckle ◽  
Fabian Franzeck ◽  
Adrian Egli ◽  
...  
Keyword(s):  
Treatment Initiation ◽  
Plasma Concentrations ◽  
Drug Level ◽  
Cytochrome P450 3A4 ◽  
Inflammation Marker ◽  
C Reactive Protein ◽  
Metabolizing Enzymes ◽  
Reactive Protein ◽  
Drug Concentrations ◽  
Study Participants

ABSTRACT Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24, and 48 h. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. The median age of study participants was 59 (range, 24 to 85) years, and 71% were male. The median durations from symptom onset to hospitalization and treatment initiation were 7 days (interquartile range [IQR], 4 to 10) and 8 days (IQR, 5 to 10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 μg/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (r = 0.37, P < 0.001) and were significantly lower when tocilizumab was preadministered. No correlation was found between HCQ concentrations and CRP values. High LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 50% effective concentrations (EC50) indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.

scholarly journals Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Seth C. Hopkins ◽  
Nina Dedic ◽  
Kenneth S. Koblan
Keyword(s):  
Clinical Trials ◽  
Rem Sleep ◽  
Therapeutic Potential ◽  
Brain Activity ◽  
Plasma Concentrations ◽  
Dose Selection ◽  
Double Blind ◽  
Drug Concentrations ◽  
Sleep Parameters

AbstractSEP-363856 is a trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) agonist, currently in Phase 3 clinical trials for the treatment of schizophrenia. Although SEP-363856 activates TAAR1 and 5-HT1A receptors in vitro, an accessible marker of time- and concentration-dependent effects of SEP-363856 in humans is lacking. In rodents, SEP-363856 has been shown to suppress rapid eye movement (REM) sleep. The aim of the current study was to translate the REM sleep effects to humans and determine pharmacokinetic/pharmacodynamic (PK/PD) relationships of SEP-363856 on a measure of brain activity. The effects of SEP-363856 were evaluated in a randomized, double-blind, placebo-controlled, 2-way crossover study of single oral doses (50 and 10 mg) on REM sleep in healthy male subjects (N = 12 at each dose level). Drug concentrations were sampled during sleep to interpolate individual subject’s pharmacokinetic trajectories. SEP-363856 suppressed REM sleep parameters with very large effect sizes (>3) following single doses of 50 mg and plasma concentrations ≥100 ng/mL. Below that effective concentration, the 10 mg dose elicited much smaller effects, increasing only the latency to REM sleep (effect size = 1). The PK/PD relationships demonstrated that REM sleep probability increased as drug concentrations declined below 100 ng/mL over the course of the night. SEP-363856 was generally safe and well tolerated at both doses. The REM sleep-suppressing effects of SEP-363856 provide an accessible marker of brain activity, which can aid in dose selection and help elucidate its therapeutic potential in further clinical trials.

Is Dilute Russell’s Viper Venom Time a Useful Assay To Monitor Patients Treated By Rivaroxaban Or Dabigatran Etexilate?

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3634-3634
Author(s):  
Jonathan Douxfils ◽  
Anne Tamigniau ◽  
Bernard Chatelain ◽  
Bérangère Devalet ◽  
Pierre Wallemacq ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Plasma Concentrations ◽  
Real Life ◽  
Drug Level ◽  
Plasma Drug Level ◽  
Thrombin Inhibitor ◽  
Plasma Drug ◽  
Drug Concentrations ◽  
Russell’S Viper ◽  
Plasma Drug Concentrations

Abstract Introduction There is still a need for a general test easily implementable and widely available that may be used to screen all patients on DOACs. A recent study has suggested that the dilute Russell Viper Venom Time (DRVV-T) could be used for the monitoring of DOACs but these results have been generated in vitro. The primary objective of this study is to analyse and compare the results obtained with the DRVV Screen and Confirm tests to the plasma drug levels measured by LC-MS/MS. We also aimed at proposing specific cut-off associated with supratherapeutic levels at Ctrough. Finally, a comparison of our results with those obtained with PT for rivaroxaban and aPTT for dabigatran is also provided. Methods Thirty-two rivaroxaban and 31 dabigatran platelet poor plasma samples from real-life patients were included in the study. Dilute Russell's Viper Venom time was measured using STA®-Staclot®DRVV Screen and Confirm reagents. Prothrombin Time and aPTT have been performed with Triniclot PT Excel S® and RecombiPlastin 2G® and with STA®C.K. Prest and SynthasIL®, respectively. The Hemoclot Thrombin Inhibitor® and the Biophen DiXaI® have been performed to estimate plasma concentration of dabigatran and rivaroxaban, respectively. All methodologies were performed on a STA-R Evolution® analyser according with the recommendation of the manufacturer, except for RecombiPlastin 2G® which were performed on an ACL-TOP®. All of these tests have been performed according to the recommendations of the manufacturer. The reference LC-MS/MS measurement of plasma drug concentrations were validated according to FDA Guidelines for Industry for Bioanalytical Method (for rivaroxaban) and to the Validation European Medicines Agency guidelines (for dabigatran). Results The plasma concentrations range from 6 to 426ng/mL for rivaroxaban and from 0 to 386ng/mL for dabigatran as determined by LC-MS/MS. Tables 1 and 2 summarize Spearman correlations and Bland-Atlman analyses for rivaroxaban and dabigatran, respectively. Figures 1 and 2 provide the results of STA®-Staclot®DRVV Screen and Confirm versus LC-MS/MS measurements. Bland-Altman graphs are also provided. Discussion STA®-Staclot®DRVV-Screen and Confirm shows a better correlation than PT or aPTT. Bland-Altman analyses reveal an overestimation of approximately 40ng/mL and large 5th-95th limits of agreement with both STA®-Staclot®DRVV-Screen and Confirm. Specific cut-offs associated with supratherapeutic level (>200ng/mL) at Ctrough have been defined. For STA®-Staclot®DRVV-Screen, results below 125 seconds or below a ratio of 3 could exclude plasma concentrations >200ng/mL for rivaroxaban and dabigatran (Figure 1 - A and B). For STA®-Staclot®DRVV-Confirm, cut-offs must be adapted independently (Figure 2 - A and B). Results below 75 seconds or below a ratio of 2, could exclude rivaroxaban plasma concentrations >200ng/mL. For dabigatran, the threshold could be defined at 90 seconds or at a ratio of 2.5. Conclusion Thanks to its good correlation with plasma drug level, DRVVT can be more informative than PT and aPTT, to exclude supra-therapeutic level of rivaroxaban and dabigatran at Ctrough. However, due to overestimations in plasma drug level, it cannot be recommended to accurately estimate plasma drug concentrations which require more specific coagulation assays or LC-MS/MS measurements. Disclosures: No relevant conflicts of interest to declare.

High-Dose Medroxyprogesterone in Disseminated Breast Cancer. Correlation between Bioavailability and Clinical Response

1987 ◽  
Vol 73 (6) ◽  
pp. 617-621 ◽  
Author(s):  
Adriano Fornasiero ◽  
Paolo Morandi ◽  
Otello Daniele ◽  
Cristina Ghiotto ◽  
Savina M.L. Aversa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Response ◽  
Remission Rate ◽  
Plasma Concentrations ◽  
Drug Level ◽  
High Dose ◽  
Breast Cancer Patients ◽  
Routes Of Administration ◽  
Group Response ◽  
Drug Plasma Levels

Clinical response to high-dose medroxyprogesterone (MPA), administered following three different routes of administration (i.m., p.o.+i.m., p.o.) and monitoring drug plasma levels, was evaluated in pretreated advanced breast cancer patients. Fifty-eight of 68 eligible patients were considered evaluable for response. Age ranged between 36 years and 82 years. Fifty-six of 58 evaluable patients were postmenopausal. An overall remission rate of 48% was achieved with i.m. MPA, 50% with combined (i.m. + p.o.) modalities; only a 19% remission rate was recorded in the p.o. group Response rate and MPA plasma concentrations were correlated, and a drug level of 80 ng/ml, by means of a GLC method, seems to identify a subset of patients with high probability of response. Only mild toxic effects were recorded.

Pharmacokinetics and Safety Assessment of Anti-HIV Dapivirine Vaginal Microbicide Rings with Multiple Dosing

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Ex Vivo ◽  
Oral Treatment ◽  
Plasma Concentrations ◽  
Vaginal Ring ◽  
Vaginal Fluid ◽  
Cervical Tissue ◽  
Double Blind ◽  
Group A ◽  
Group B ◽  
Anti Hiv

Objectives: Self-administered vaginal rings are a promising method for delivery of topical anti-HIV microbicidesand might offer an adherence advantage over daily or coitally-dependent dosage forms such as gels. This trialassessed the safety and pharmacokinetic aspects of the Dapivirine Vaginal Ring-004 when worn as multiple rings oversequential periods of ring use by healthy, sexually-active, HIV-negative women.Methods: This double-blind trial was conducted among 48 women (18-40 years). Participants were randomlyassigned to two groups (A or B) and received (3:1) either the dapivirine or a placebo vaginal ring. Group A used tworings over a 56-day period and Group B used three rings over a 57-day period. Safety evaluations were conductedthroughout the trial. Dapivirine concentrations were measured in plasma, vaginal fluid and cervical tissue samplescollected during and after the 56 days (Group A) or 57 days (Group B) of vaginal ring use.Results: Ring-004 was safe and well tolerated in all participants. The pharmacokinetic profile demonstrated arapid increase in plasma and vaginal fluid concentrations and achieved concentrations in vaginal fluids and cervicaltissue well above the in vitro IC99 in cervical tissue (3.3 ng/mL) that were sustained for a 28 to 35-day ring use period(approximately 3000 times higher in vaginal fluids and 14 -1000 times higher in cervical tissue). Drug levels wereassociated with significant inhibitory activity of genital secretions against HIV ex vivo, a biomarker of pharmacodynamics.Individual plasma dapivirine concentrations did not exceed 553 pg/mL and were well below plasma concentrations atthe maximum tolerated dose for oral treatment (mean Cmax 2286 ng/mL).Conclusions: The consecutive use of several rings over a period of up to 57 days was safe and well tolerated, andPK data indicate that a single Ring-004 is likely to be protective for at least 35 days.

Clinical Impact of Co-medication of Levetiracetam and Clobazam with Proton Pump Inhibitors: A Drug Interaction Study

2020 ◽  
Vol 21 (2) ◽  
pp. 126-131
Author(s):  
Bhuvanachandra Pasupuleti ◽  
Vamshikrishna Gone ◽  
Ravali Baddam ◽  
Raj Kumar Venisetty ◽  
Om Prakash Prasad
Keyword(s):  
Plasma Concentration ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Plasma Concentrations ◽  
Control Group ◽  
Drug Concentrations ◽  
Significant Difference ◽  
Post Hoc ◽  
Hydrolysis Of ◽  
Cytochrome P 450

Background: Clobazam (CLBZ) metabolized primarily by Cytochrome P-450 isoenzyme CYP3A4 than with CYP2C19, Whereas Levetiracetam (LEV) is metabolized by hydrolysis of the acetamide group. Few CYP enzymes are inhibited by Proton Pump Inhibitors (PPIs) Pantoprazole, Esomeprazole, and Rabeprazole in different extents that could affect drug concentrations in blood. The aim of the present study was to evaluate the effect of these PPIs on the plasma concentrations of LEV and CLBZ. Methods: Blood samples from 542 patients were included out of which 343 were male and 199 were female patients and were categorized as control and test. Plasma samples analyzed using an HPLC-UV method. Plasma concentrations were measured and compared to those treated and those not treated with PPIs. One way ANOVA and games Howell post hoc test used by SPSS 20 software. Results: CLBZ concentrations were significantly 10 folds higher in patients treated with Pantoprazole (P=0.000) and 07 folds higher in patients treated with Esmoprazole and Rabeprazole (P=0.00). Whereas plasma concentration of LEV control group has no statistical and significant difference when compared to pantoprazole (P=0.546) and with rabeprazole and esomeprazole was P=0.999. Conclusion: The effect of comedication with PPIs on the plasma concentration of clobazam is more pronounced for pantoprazole to a greater extent when compared to esomeprazole and rabeprazole. When pantoprazole is used in combination with clobazam, dose reduction of clobazam should be considered, or significance of PPIs is seen to avoid adverse effects.

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