Penetration of Intravenous and Oral Ciprofloxacin into Sterile and Empyemic Human Pleural Fluid

1994 ◽  
Vol 28 (3) ◽  
pp. 313-315 ◽  
Author(s):  
Joe Joseph ◽  
Leigh M. Vaughan ◽  
Gurnam S. Basran
Keyword(s):  
Steady State ◽  
Pleural Fluid ◽  
Venous Blood ◽  
Plasma Concentrations ◽  
Prospective Trial ◽  
Pleural Effusions ◽  
Open Label ◽  
Plasma Ratio ◽  
Oral Ciprofloxacin ◽  
Oral Doses

OBJECIVE: To compare the penetration of oral and intravenously administered ciprofloxacin into infected (empyemic) and noninfected(sterile) human pleural fluid. DESIGN: Eleven men and 5 women (aged 29–76) were consecutivelyselected from adult patients referred to the respiratory unit forpleural effusion. In this open-label, prospective trial, 13 patients withsterile pleural effusions were nonrandomly assigned to receive eitherciprofloxacin 200 mg (single intravenous dose), 750 mg (single oraldose), or 750 mg (two oral doses per day for 3 days); 3 patients withinfected pleural effusions received 750 mg oral doses for 10 days. Simultaneous pleural fluid and venous blood specimens were drawnover 5 hours after single dose or when steady-state was attained, andciprofloxacin concentrations were measured by HPLC. RESULTS: Pleural fluid concentrations of ciprofloxacin equaledplasma concentrations 1.5 hours after 200 mg was givenintravenously and the pleural/plasma ratio remained ∼ 0.9 for 4hours. After a single 750-mg oral dose, pleural ciprofloxacinconcentrations rose from 0 to 1.4 ug/ml, over 5 hours with thehighest pleural fluid/plasma ratio (0.7) at 5 hours. Average steadystateciprofloxacin concentrations in sterile pleural fluid after 750mg administered twice daily for 3 days, ranged between 1.1 and 1.8ug/rnl, with ratios between 0.3 and 0.9 over 4 hours. In empyemicpleural fluid at the same dosage, average steady-state ciprofloxacinconcentrations ranged between 1.9 and 3.4 ug/ml, with ratiosbetween 1.0 and 2.0 over 5 hours. CONCLUSIONS: Oral ciprofloxacin penetrates into sterile andempyemic pleural fluid with concentrations 30–90 percent and100–200 percent of plasma concentrations, respectively.

scholarly journals Lack of Effect of Efavirenz on the Pharmacokinetics of Tipranavir-Ritonavir in Healthy Volunteers

2009 ◽  
Vol 53 (11) ◽  
pp. 4840-4844 ◽  
Author(s):  
C. J. L. la Porte ◽  
J. P. Sabo ◽  
L. Béïque ◽  
D. W. Cameron
Keyword(s):  
Steady State ◽  
Multiple Dose ◽  
Healthy Adult ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Open Label ◽  
Multiple Dose Study ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Dose Study

ABSTRACT Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) plasma concentrations. This study investigates the effect of steady-state EFV on steady-state TPV/r pharmacokinetics. This was a single-center, open-label, multiple-dose study of healthy adult female and male volunteers. TPV/r 500/200 mg twice a day (BID) was given with food for 24 days. After dosing with TPV/r for 10 days, EFV 600 mg once a day was added to the regimen. Intensive pharmacokinetic (PK) sampling was done on days 10 and 24. Validated bioanalytical high-pressure liquid chromatography-tandem mass spectrometry methods were used to determine plasma tipranavir (TPV), ritonavir (RTV), and EFV concentrations. Thirty-four subjects were entered into the study, and 16 subjects completed it. The geometric mean ratios (90% confidence intervals) for TPV and RTV area under the curves, C maxs, and C mins comparing TPV/r alone and in combination with EFV were 0.97 (0.87 to 1.09), 0.92 (0.81 to 1.03), and 1.19 (0.93 to 1.54) for TPV and 1.03 (0.78 to 1.38), 0.92 (0.65 to 1.30), and 1.04 (0.72 to 1.48) for RTV. Frequently observed adverse events were diarrhea, headache, dizziness, abnormal dreams, and rash. EFV had no effect on the steady-state PK of TPV or RTV, with the exception of a 19% increase in the TPV C min, which is not clinically relevant. TPV/r can be safely coadministered with EFV and without the need for a dose adjustment.

scholarly journals Pharmacokinetics of Different Dosing Strategies of Oral Posaconazole in Patients with Compromised Gastrointestinal Function and Who Are at High Risk for Invasive Fungal Infection

2012 ◽  
Vol 56 (5) ◽  
pp. 2652-2658 ◽  
Author(s):  
Oliver A. Cornely ◽  
David Helfgott ◽  
Amelia Langston ◽  
Werner Heinz ◽  
Jörg-Janne Vehreschild ◽  
...  
Keyword(s):  
Steady State ◽  
High Risk ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Nutritional Supplement ◽  
Gastrointestinal Function ◽  
Open Label ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Poor Absorption

ABSTRACTThe aim of this study was to assess different dosing strategies that may result in increased posaconazole bioavailability in patients with compromised gastrointestinal function and at high risk for invasive fungal infections. Patients undergoing chemotherapy and at risk for compromised gastrointestinal function received open-label posaconazole at 200 mg three times daily (TID) on days 1 to 8. Patients were randomized to one of three open-label dosing regimens of posaconazole on days 9 to 15: 200 mg TID, 400 mg twice daily (BID), or 400 mg TID. The plasma concentrations of interest on days 8 and 15 were 500 and 700 ng/ml, respectively; day 2 plasma concentrations of 250 and 350 ng/ml were chosen as levels that might result in steady-state concentrations of >500 and >700 ng/ml, respectively. A total of 75 patients enrolled; 52/75 (69%) completed the study, and 49/75 were included in the pharmacokinetic analyses. Mean plasma concentrations were 230, 346, and 637 ng/ml on days 2, 3, and 8, respectively. The day 15 values were 660, 930, and 671 ng/ml for 200 mg TID, 400 mg BID, and 400 mg TID, respectively. In 12 patients with a day 8 posaconazole concentration of <250 ng/ml, an overall benefit of the higher two doses was not apparent, suggesting that a subset of patients has low steady-state plasma concentrations. A change in dosing regimen on day 9 did not lead to higher exposures in these “poor absorbers” on day 15. Poor absorption may be enhanced with a high-fat meal, a nutritional supplement, or acidification.

Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura

2011 ◽  
Vol 105 (03) ◽  
pp. 545-552 ◽  
Author(s):  
Bernd Jilma ◽  
Jolanta Siller-Matula ◽  
James Gilbert ◽  
Paul Knöbl ◽  
Petra Jilma-Stohlawetz ◽  
...  
Keyword(s):  
Steady State ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Plasma Concentrations ◽  
Prospective Trial ◽  
Organ Damage ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Thrombocytopenic Purpura ◽  
Platelet Counts ◽  
Baseline Activity ◽  
Von Willebrand

SummaryThrombotic thrombocytopenic purpura (TTP) can cause severe organ damage due to enhanced platelet aggregation by ultra-large von Wille-brand factor (VWF) multimers. Thus inhibition of VWF by the anti-VWF ARC1779 might potentially be beneficial for TTP patients. This prospective trial tested the safety, pharmacokinetics and pharmacodynamics of the anti-VWF aptamer ARC1779 added to plasma exchange therapy (PEX) in patients with acute TTP. Seven patients received bolus primed continuous i.v. infusions of ARC1779 (1–2 μg/kg/min) in addition to PEX until remission of TTP was induced or for 14 days. Mean steady state ARC1779 plasma concentrations of 9.9 μg/ml reduced VWF activity to 5% (mean baseline activity was 125% in TTP patients compared to a reference plasma). PEX reduced ARC1779 levels by 50%, but steady state concentrations were restored rapidly with a mini-bolus. After discontinuation of PEX, ARC1779 alone further increased platelet counts in one patient. Stopping ARC1779 was associated with an immediate drop of platelet counts in this patient. This suggests that ARC1779 can block the progression of TTP in patients with severe ADAMTS13 is deficiency. ARC1779 was generally well tolerated without any signs of bleeding. Pharmacokinetics and pharmacodynamics of ARC1779 were well predictable and in agreement with those observed in a previous trial with healthy volunteers. Based on its mechanism of action and the observed effect on platelet counts, ARC1779 used as an adjunctive to PEX may help accelerate recovery from organ dysfunction.

scholarly journals Pharmacokinetic Study of Human Immunodeficiency Virus Protease Inhibitors Used in Combination with Amprenavir

2001 ◽  
Vol 45 (12) ◽  
pp. 3663-3668 ◽  
Author(s):  
Brian M. Sadler ◽  
Catherine Gillotin ◽  
Yu Lou ◽  
Joseph J. Eron ◽  
William Lang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Protease Inhibitors ◽  
Pharmacokinetic Study ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Immunodeficiency Virus

ABSTRACT In an open-label, randomized, multicenter, multiple-dose pharmacokinetic study, we determined the steady-state pharmacokinetics of amprenavir with and without coadministration of indinavir, nelfinavir, or saquinavir soft gel formulation in 31 human immunodeficiency virus type 1-infected subjects. The results indicated that amprenavir plasma concentrations were decreased by saquinavir soft gel capsule (by 32% for area under the concentration-time curve at steady state [AUCss] and 37% for peak plasma concentration at steady state [C max,ss]) and increased by indinavir (33% for AUCss). Nelfinavir significantly increased amprenavir minimum drug concentration at steady state (by 189%) but did not affect amprenavir AUCss orC max,ss. Nelfinavir and saquinavir steady-state pharmacokinetics were unchanged by coadministration with amprenavir compared with the historical monotherapy data. Concentrations of indinavir, coadministered with amprenavir, in plasma decreased in both single-dose and steady-state evaluations. The changes in amprenavir steady-state pharmacokinetic parameters, relative to those for amprenavir alone, were not consistent among protease inhibitors, nor were the changes consistent with potential interactions in CYP3A4 metabolism or P-glycoprotein transport. No dose adjustment of either protease inhibitor in any of the combinations studied is needed.

scholarly journals The Effect of Undaria pinnatifida Fucoidan on the Pharmacokinetics of Letrozole and Tamoxifen in Patients With Breast Cancer

2016 ◽  
Vol 17 (1) ◽  
pp. 99-105 ◽  
Author(s):  
Shreya Tocaciu ◽  
Lesley J. Oliver ◽  
Ray M. Lowenthal ◽  
Gregory M. Peterson ◽  
Rahul Patel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Steady State ◽  
High Performance ◽  
Undaria Pinnatifida ◽  
Plasma Concentrations ◽  
Concomitant Administration ◽  
Open Label ◽  
Concurrent Use ◽  
Charged Aerosol ◽  
Hormonal Therapies

Background: Although the use of complementary and alternative medicines is widespread in cancer patients, clinical evidence of their benefits is sparse. Furthermore, while they are often assumed to be safe with regard to concurrent use of anticancer therapies, few studies have been carried out to investigate possible interactions. Fucoidans are a group of sulfated carbohydrates, derived from marine brown algae, which have long been used as dietary supplements due to their reported medicinal properties, including anticancer activity. The aim of this study was to investigate the effect of co-administration of fucoidan, derived from Undaria pinnatifida, on the pharmacokinetics of 2 commonly used hormonal therapies, letrozole and tamoxifen, in patients with breast cancer. Methods: This was an open label non-crossover study in patients with active malignancy taking letrozole or tamoxifen (n = 10 for each group). Patients took oral fucoidan, given in the form of Maritech extract, for a 3-week period (500 mg twice daily). Trough plasma concentrations of letrozole, tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using HPLC-CAD (high-performance liquid chromatography charged aerosol detector), at baseline and after concomitant administration with fucoidan. Results: No significant changes in steady-state plasma concentrations of letrozole, tamoxifen, or tamoxifen metabolites were detected after co-administration with fucoidan. In addition, no adverse effects of fucoidan were reported, and toxicity monitoring showed no significant differences in all parameters measured over the study period. Conclusions: Administration of Undaria pinnatifida fucoidan had no significant effect on the steady-state trough concentrations of letrozole or tamoxifen and was well tolerated. These results suggest that fucoidan in the studied form and dosage could be taken concomitantly with letrozole and tamoxifen without the risk of clinically significant interactions.

scholarly journals Impact of Rifabutin or Rifampin on Bedaquiline Safety, Tolerability, and Pharmacokinetics Assessed in a Randomized Clinical Trial with Healthy Adult Volunteers

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Amanda M. Healan ◽  
J. McLeod Griffiss ◽  
Howard M. Proskin ◽  
Mary Ann O'Riordan ◽  
Wesley A. Gray ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Adult ◽  
Controlled Trial ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Parameter Estimates ◽  
Open Label ◽  
Combination Drug ◽  
Period 2 ◽  
Adult Volunteers

ABSTRACT Bedaquiline is a diarylquinoline that specifically inhibits mycobacterial ATP synthase. Bedaquiline has been used to effectively treat tuberculosis (TB) caused by drug-susceptible and drug-resistant Mycobacterium tuberculosis. Rifamycins are a cornerstone of combination drug regimens for the treatment of TB. This phase 1, open-label, randomized, controlled trial evaluated the effect of steady-state dosing of rifabutin or rifampin on the safety, tolerability, and pharmacokinetics of bedaquiline given as a single dose. Thirty-three healthy subjects were enrolled to receive a 400-mg single oral dose of bedaquiline at two time points, on study days 1 and 29. Subjects were randomly assigned to once daily oral doses of rifabutin (300 mg/day, n = 17) or rifampin (600 mg/day, n = 16) during period 2 from days 20 to 41. Serial blood sampling for bedaquiline measurement occurred on days 1 and 29 through 336 h after bedaquiline administration. The day 29 bedaquiline pharmacokinetic parameter estimates were compared to the corresponding day 1 estimates for each rifamycin group. Steady-state rifampin reduced bedaquiline AUC0–336 approximately 45%, from 47.69 h·μg/ml in period 1 to 26.33 h·μg/ml in period 2. Bedaquiline apparent clearance accelerated 24% in rifampin-treated subjects from 6.59 liters/h in period 1 to 8.19 liters/h in period 2. Steady-state rifabutin resulted in little quantitative impact on bedaquiline exposure but was associated with grade 3 and 4 adverse events before and after the day 29 bedaquiline dose. Dosage adjustments may therefore be necessary to ensure that bedaquiline plasma concentrations reach therapeutic levels safely when combining bedaquiline and rifamycins in TB treatment regimens. (This single-site, randomized, open-label, prospective study in healthy adult volunteers was registered at Clinicaltrials.gov under registration no. NCT01341184.)

Uptake and distribution of halothane in dog blood

1980 ◽  
Vol 58 (9) ◽  
pp. 1078-1085 ◽  
Author(s):  
Y. C. Pang ◽  
P. E. Reid ◽  
D. E. Brooks ◽  
K. M. Leighton ◽  
C. Bruce
Keyword(s):  
Steady State ◽  
Partial Pressure ◽  
Venous Blood ◽  
Plasma Concentrations ◽  
Direct Analysis ◽  
Mixed Venous Blood ◽  
Arterial Blood ◽  
Halothane Concentration ◽  
Dog Blood ◽  
End Tidal

The uptake and distribution of halothane in dog blood were studied by analysing the whole blood and plasma concentrations of halothane in samples of arterial and mixed venous blood at different times after the induction of anesthesia with constant inspired halothane levels of 1.0, 1.5, 2.0, and 2.5%, respectively. In general a steady state was reached 2–3 h after induction. Comparison of the arterial blood concentration calculated from end-tidal halothane partial pressure with that determined by direct analysis of the blood indicated that halothane in the alveoli and halothane in arterial blood are not in thermodynamic equilibrium. The arterial halothane concentrations calculated from the end-tidal halothane partial pressure assuming equilibrium is much higher than those found experimentally; thus end-tidal halothane partial pressure is not a true measure of blood halothane concentration. The distribution of halothane between the plasma and cells in blood appeared to be sufficiently rapid to be independent of the approach to the steady state.

A pharmacokinetic evaluation of single and multiple doses of extended-release hydrocodone bitartrate in subjects experiencing surgical or osteoarthritic pain

2015 ◽  
Vol 11 (5) ◽  
pp. 405 ◽  
Author(s):  
Cynthia Y. Robinson, PhD ◽  
Christopher M. Rubino, PharmD ◽  
Stephen J. Farr, PhD
Keyword(s):  
Single Dose ◽  
Steady State ◽  
Extended Release ◽  
Venous Blood ◽  
Plasma Concentrations ◽  
Immediate Release ◽  
Pharmacokinetic Parameters ◽  
Single Dose Study ◽  
Dosing Interval ◽  
Osteoarthritic Pain

Objectives: To assess the single-dose and steady-state pharmacokinetics of a single-entity hydrocodone extended-release (ER) formulation in patients enrolled in two separate phase 2 clinical studies.Setting: Both studies were multicenter clinical studies.Subjects and interventions: In study 1, 115 subjects with postsurgical pain (bunionectomy) received single doses of 10, 20, 30, or 40 mg hydrocodone-ER, 10 mg hydrocodone/325 mg acetaminophen immediate-release (IR), or placebo. In study 2, 37 subjects with osteoarthritic pain received doses of 10, 20, 30, or 40 mg of hydrocodone-ER twice-daily for 7 days. Venous blood samples were taken periodically up to 24 hours postdosing after the single dose (study 1) or after 7 days of dosing (study 2) and were assayed for concentrations of hydrocodone and its major metabolites.Main outcome measures: Standard pharmacokinetic parameters were estimated by noncompartmental analysis methods.Results: Following a single dose of hydrocodone-ER, Tmax was prolonged to approximately 6 hours at all dose levels of hydrocodone-ER compared with 2.9 hours for the IR formulation. All doses of hydrocodone-ER formulations provided prolonged and sustained release of hydrocodone throughout the 12-hour dosing interval with reduced peak-to-trough fluctuation at steady state compared with hydrocodone/acetaminophen-IR comparator. Both single-dose and steady-state mean Cmax and AUClast values showed reasonable dose-proportionality. Norhydrocodone and hydromorphone plasma concentrations were 32-38 percent and <2.1 percent, respectively, of hydrocodone concentrations in both studies.Conclusions: The sustained plasma concentrations of hydrocodone support twice-daily dosing with a 12-hour dosing interval.

An Open, Phase I Study of Cediranib in Patients with Acute Myeloid Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 895-895
Author(s):  
Walter Fiedler ◽  
Rolf Mesters ◽  
Michael Heuser ◽  
Gerhard Ehninger ◽  
Oliver G. Ottman ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Steady State ◽  
Dose Escalation ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Biologically Active ◽  
Minor Response ◽  
Once Daily ◽  
Oral Doses ◽  
Refractory Aml

Abstract Prognosis is poor for the majority of AML patients, particularly the elderly and those with relapsed or refractory AML, and more effective treatment options are needed. Vascular endothelial growth factor-A (VEGF) and its receptors (VEGFRs) may contribute to the pathophysiology of AML and are considered as potential therapeutic targets. Cediranib (RECENTIN™; AZD2171) is an oral, highly potent and selective VEGF signaling inhibitor with activity versus VEGFR-1, -2 and -3, and additional activity against c-Kit. This two-part study evaluated the safety and tolerability of multiple once-daily oral doses of cediranib in patients with relapsed or refractory AML and elderly patients with de novo or secondary AML, with secondary assessments of pharmacokinetics (PK), pharmacodynamics (PD) and efficacy. Part A was a dose-escalation phase to determine the maximum tolerated dose (MTD); Part B was an expansion phase to explore the MTD and a lower, biologically active dose. A total of 35 patients (mean age, 68 years [range 50–81]; 15 male, 20 female) entered the study and received treatment with cediranib (Part A, n=23; Part B, n=12). Part A comprised 10mg (n=4), 20mg (n=6) and 30mg (n=13) dose cohorts, and intra-patient dose escalation was permitted. In Part B, patients received cediranib 20mg (n=3) or 30mg (n=9). Cediranib ≤30mg was generally well tolerated; diarrhea (n=19), hypertension (n=14) and fatigue (n=13) were the most common adverse events (AEs). Cediranib 30mg was the highest dose studied, and was declared the MTD based on dose-limiting toxicities of hypertension and diarrhea experienced by 3 patients receiving 30mg in Part A. Maximal plasma concentrations at steady-state were attained 0.83–4.1 h post-dosing. Steady-state plasma concentrations were attained after approximately 7 days of repeated once-daily dosing. Following multiple oral doses of cediranib 30mg in Parts A and B, the unbound geometric mean Css,min was 5x the IC50 value required to inhibit proliferation of human umbilical vein endothelial cells in preclinical assays, supporting the once-daily oral dosing regimen. The relationship between PK and two PD parameters (VEGF levels and blood pressure) were investigated and there appeared to be a positive correlation between exposure (Css,max and AUCss) and plasma VEGF levels, but not blood pressure. Time-dependent changes in soluble VEGFR-2 levels were observed. A best investigator assessment of AML objective response according to predefined criteria (Cheson et al, J Clin Oncol2003;21:4642–9) was observed for 6 patients (1 morphological complete remission with incomplete blood recovery [Cri], 4 partial responses and 1 minor response). However, none of the responses resulted in improvement in normal hemopoiesis. No responses were observed in 6 patients with Flt-3 ITD mutations. One patient remained on treatment for 455 days. Once-daily oral cediranib ≤30mg was generally well tolerated in patients with AML, with encouraging preliminary evidence of activity as a monotherapy. The AE and PK profiles of cediranib in AML are consistent with those seen in solid tumors.

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