The disposition of TCNU (tauromustine) in human malignant glioma: pharmacokinetic studies and clinical implications

1990 ◽  
Vol 72 (5) ◽  
pp. 721-725 ◽  
Author(s):  
Ian R. Whittle ◽  
Janet S. MacPherson ◽  
J. Douglas Miller ◽  
John F. Smyth
Keyword(s):  
Malignant Glioma ◽  
High Performance ◽  
Peak Plasma ◽  
Linear Regression Analysis ◽  
Plasma Concentrations ◽  
Tissue Level ◽  
Pharmacokinetic Studies ◽  
Tissue Concentrations ◽  
Content Type ◽  
Chromatography Analysis

✓ Tauromustine (TCNU), 130 mg/sq m, was administered intraoperatively by nasogastric tube to 10 patients with malignant glioma (seven glioblastomas and three anaplastic astrocytomas). High-performance liquid chromatography analysis of 32 tumor specimens for TCNU revealed that tissue concentrations ranged from 0 to 554 ng/gm; TCNU was not detected in necrotic regions of the tumor. Levels of TCNU in brain adjacent to tumor were similar to those recorded within the gliomas (range 0 to 635 ng/gm). The variability in the tissue level of TCNU was partly attributable to variable absorption of the drug, since peak plasma TCNU levels ranged from 164 to 3333 ng/ml. There were close quantitative and temporal relationships between the times of peak plasma levels (median 456 ng/ml at 45 minutes after administration), peak tumor levels (median 250 ng/gm tissue at 55 minutes), and brain adjacent to tumor levels (median 256 ng/gm tissue at 50 minutes). Linear regression analysis of the ratio between tissue and plasma TCNU levels at particular times after drug administration suggest that plasma concentrations can be used to estimate tissue concentrations. This study demonstrates that TCNU enters malignant glioma. In view of the activity of TCNU against a range of tumors, a full clinical evaluation of this new nitrosourea in malignant glioma seems justified.

Phase I trial of taxol given as a 24-hour infusion every 21 days: responses observed in metastatic melanoma.

1987 ◽  
Vol 5 (8) ◽  
pp. 1232-1239 ◽  
Author(s):  
P H Wiernik ◽  
E L Schwartz ◽  
A Einzig ◽  
J J Strauman ◽  
R B Lipton ◽  
...  
Keyword(s):  
Phase I ◽  
High Performance ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Hplc Method ◽  
Microtubule Assembly ◽  
Pharmacokinetic Studies ◽  
Significant Activity ◽  
Recommended Phase Ii Dose

Taxol, a plant product, has significant activity against certain rodent and human xenograft tumors. It promotes microtubule assembly in vitro, in contrast to vinca alkaloids, which inhibit assembly. In this phase I study, taxol was administered as a 24-hour continuous intravenous (IV) infusion in 65 courses to 26 patients. A premedication regimen of dexamethasone, cimetidine, and diphenhydramine was used to prevent the acute hypersensitivity reactions observed in previous studies of taxol. Only one episode of mild stridor occurred in this study. Peripheral neuropathy was the dose-limiting toxicity and was observed in 40% of patients treated at a dose of 250 mg/m2. Significant neutropenia of brief duration was also common. Pharmacokinetic studies by a high-performance liquid chromatography (HPLC) method demonstrated that drug plasma concentrations increased during the 24-hour infusion and then declined rapidly. Peak plasma concentrations correlated with dose, and less than 5% of taxol was excreted in the urine. Most of the drug was bound to serum components. Partial responses of more than 3 months' duration were observed in four of 12 melanoma patients treated. The recommended phase II dose of taxol on this schedule is 250 mg/m2. Priority should be given to the study of taxol in melanoma.

scholarly journals Physiologically Based Pharmacokinetic Model of Rifapentine and 25-Desacetyl Rifapentine Disposition in Humans

2016 ◽  
Vol 60 (8) ◽  
pp. 4860-4868
Author(s):  
Todd J. Zurlinden ◽  
Garrett J. Eppers ◽  
Brad Reisfeld
Keyword(s):  
Time Course ◽  
Pbpk Model ◽  
Plasma Concentrations ◽  
Optimal Dose ◽  
Tissue Level ◽  
Pharmacokinetic Data ◽  
Rat Tissues ◽  
Content Type ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

ABSTRACTRifapentine (RPT) is a rifamycin antimycobacterial and, as part of a combination therapy, is indicated for the treatment of pulmonary tuberculosis (TB) caused byMycobacterium tuberculosis. Although the results from a number of studies indicate that rifapentine has the potential to shorten treatment duration and enhance completion rates compared to other rifamycin agents utilized in antituberculosis drug regimens (i.e., regimens 1 to 4), its optimal dose and exposure in humans are unknown. To help inform such an optimization, a physiologically based pharmacokinetic (PBPK) model was developed to predict time course, tissue-specific concentrations of RPT and its active metabolite, 25-desacetyl rifapentine (dRPT), in humans after specified administration schedules for RPT. Starting with the development and verification of a PBPK model for rats, the model was extrapolated and then tested using human pharmacokinetic data. Testing and verification of the models included comparisons of predictions to experimental data in several rat tissues and time course RPT and dRPT plasma concentrations in humans from several single- and repeated-dosing studies. Finally, the model was used to predict RPT concentrations in the lung during the intensive and continuation phases of a current recommended TB treatment regimen. Based on these results, it is anticipated that the PBPK model developed in this study will be useful in evaluating dosing regimens for RPT and for characterizing tissue-level doses that could be predictors of problems related to efficacy or safety.

Single-dose pharmacokinetics of orally administered terbinafine in bearded dragons (Pogona vitticeps) and the antifungal susceptibility patterns of Nannizziopsis guarroi

2021 ◽  
pp. 1-8
Author(s):  
Michael S. McEntire ◽  
Jennifer M. Reinhart ◽  
Sherry K. Cox ◽  
Krista A. Keller
Keyword(s):  
Single Dose ◽  
High Performance ◽  
Clinical Decision Making ◽  
Peak Plasma ◽  
Antifungal Susceptibility ◽  
Plasma Concentrations ◽  
Clinical Decision ◽  
Oral Solution ◽  
Susceptibility Data ◽  
Pogona Vitticeps

Abstract OBJECTIVE To identify the antifungal susceptibility of Nanniziopsis guarroi isolates and to evaluate the single-dose pharmacokinetics of orally administered terbinafine in bearded dragons. ANIMALS 8 healthy adult bearded dragons. PROCEDURES 4 isolates of N guarroi were tested for antifungal susceptibility. A compounded oral solution of terbinafine (25 mg/mL [20 mg/kg]) was given before blood (0.2 mL) was drawn from the ventral tail vein at 0, 4, 8, 12, 24, 48, 72, and 96 hours after administration. Plasma terbinafine concentrations were measured with high-performance liquid chromatography. RESULTS The antifungal minimum inhibitory concentrations against N guarroi isolates ranged from 4,000 to > 64,000 ng/mL for fluconazole, 125 to 2,000 ng/mL for itraconazole, 125 to 2,000 ng/mL for ketoconazole, 125 to 1,000 ng/mL for posaconazole, 60 to 250 ng/mL for voriconazole, and 15 to 30 ng/mL for terbinafine. The mean ± SD peak plasma terbinafine concentration in bearded dragons was 435 ± 338 ng/mL at 13 ± 4.66 hours after administration. Plasma concentrations remained > 30 ng/mL for > 24 hours in all bearded dragons and for > 48 hours in 6 of 8 bearded dragons. Mean ± SD terminal half-life following oral administration was 21.2 ± 12.40 hours. CLINICAL RELEVANCE Antifungal susceptibility data are available for use in clinical decision making. Results indicated that administration of terbinafine (20 mg/kg, PO, q 24 to 48 h) in bearded dragons may be appropriate for the treatment of dermatomycoses caused by N guarroi. Clinical studies are needed to determine the efficacy of such treatment.

scholarly journals Plasma and tissue clindamycin antimicrobial activity after parenteral administration to cats under surgical conditions

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Sabrina Passini ◽  
Laura Montoya ◽  
Martín Lupi ◽  
Paula Lorenzini ◽  
María Fabiana Landoni ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Subcutaneous Tissue ◽  
Plasma Concentrations ◽  
Subcutaneous Administration ◽  
Dose Interval ◽  
Tissue Concentrations ◽  
Administration Routes ◽  
Infection Treatment ◽  
Plasma Concentration Ratio ◽  
Surgical Conditions

Clindamycin plasma and tissue disposition in cats under surgical conditions after a single intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration at a dose rate of 10 mg/kg were studied. After intravenous, intramuscular and subcutaneous administration, peak plasma concentrations were 10.93±3.78 μg/mL (Cp(0)), 5.93±1.18 μg/mL (Cmax)) and 6.30±0.88 μg/mL (Cmax)), respectively. Eight hours after clindamycin IV, IM and SC administration plasma concentrations declined to 2.01±0.61 μg/mL, 2.96±0.43 μg/mL and 3.36±0.97 μg/mL, respectively. Sixty to 90 minutes after clindamycin administration, tissue concentrations ranged from a minimum in subcutaneous tissue of 4.90 μg/g (IV), 3.06 μg/g (IM) and, 3.13 μg/g (SC) to a maximum in uterus of 13.41 μg/g (IV), 14.07 μg/g (IM) and, 14.44 μg/g (SC). The lowest tissue/plasma concentration ratio for the three administration routes was observed in subcutaneous tissue, while the highest was observed at genital level (ovary for IV and IM and uterus for SC). Estimated efficacy predictor (AUC/MIC), considering MIC breakpoint for bacteria isolated from animals, indicates that clindamycin administered IV, IM or SC at the studied dose is appropriated for perioperative prophylactic protocols and that given with a dose interval of 12 hours would be effective for susceptible infection treatment in cats.

scholarly journals Comparative Profiling and Discovery of Novel Glycosylated Mycosporine-Like Amino Acids in Two Strains of the Cyanobacterium Scytonema cf. crispum

2016 ◽  
Vol 82 (19) ◽  
pp. 5951-5959 ◽  
Author(s):  
Paul M. D'Agostino ◽  
Vivek S. Javalkote ◽  
Rabia Mazmouz ◽  
Russell Pickford ◽  
Pravin R. Puranik ◽  
...  
Keyword(s):  
Amino Acids ◽  
New Zealand ◽  
Uv Radiation ◽  
High Performance ◽  
Parent Compound ◽  
Future Research ◽  
Content Type ◽  
Chromatography Analysis ◽  
Paralytic Shellfish Toxins ◽  
Cell Extracts

ABSTRACTThe mycosporine-like amino acids (MAAs) are a group of small molecules with a diverse ecological distribution among microorganisms. MAAs have a range of physiological functions, including protection against UV radiation, making them important from a biotechnological perspective. In the present study, we identified a putative MAA (mys) gene cluster in two New Zealand isolates ofScytonemacf.crispum(UCFS10 and UCFS15). Homology to “Anabaena-type”mysclusters suggested that this cluster was likely to be involved in shinorine biosynthesis. Surprisingly, high-performance liquid chromatography analysis ofS. cf.crispumcell extracts revealed a complex MAA profile, including shinorine, palythine-serine, and their hexose-bound variants. It was hypothesized that a short-chain dehydrogenase (UCFS15_00405) encoded by a gene adjacent to theS. cf.crispummyscluster was responsible for the conversion of shinorine to palythine-serine. Heterologous expression of MysABCE and UCFS15_00405 inEscherichia coliresulted in the exclusive production of the parent compound shinorine. Taken together, these results suggest that shinorine biosynthesis inS. cf.crispumproceeds via anAnabaena-type mechanism and that the genes responsible for the production of other MAA analogues, including palythine-serine and glycosylated analogues, may be located elsewhere in the genome.IMPORTANCERecently, New Zealand isolates ofS. cf.crispumwere linked to the production of paralytic shellfish toxins for the first time, but no other natural products from this species have been reported. Thus, the species was screened for important natural product biosynthesis. The mycosporine-like amino acids (MAAs) are among the strongest absorbers of UV radiation produced in nature. The identification of novel MAAs is important from a biotechnology perspective, as these molecules are able to be utilized as sunscreens. This study has identified two novel MAAs that have provided several new avenues of future research related to MAA genetics and biosynthesis. Further, we have revealed that the genetic basis of MAA biosynthesis may not be clustered on the genome. The identification of the genes responsible for MAA biosynthesis is vital for future genetic engineering.

Exercise-dependent growth hormone release is linked to markers of heightened central adrenergic outflow

2000 ◽  
Vol 89 (2) ◽  
pp. 629-635 ◽  
Author(s):  
Arthur Weltman ◽  
Cathy J. Pritzlaff ◽  
Laurie Wideman ◽  
Judy Y. Weltman ◽  
Jeffery L. Blumer ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Regression Analysis ◽  
Exercise Intensity ◽  
Acute Exercise ◽  
Peak Plasma ◽  
Linear Regression Analysis ◽  
Plasma Concentrations ◽  
Intensity Change ◽  
Plasma Norepinephrine ◽  
The Difference

To test the hypothesis that heightened sympathetic outflow precedes and predicts the magnitude of the growth hormone (GH) response to acute exercise (Ex), we studied 10 men [age 26.1 ± 1.7 (SE) yr] six times in randomly assigned order (control and 5 Ex intensities). During exercise, subjects exercised for 30 min (0900–0930) on each occasion at a single intensity: 25 and 75% of the difference between lactate threshold (LT) and rest (0.25LT, 0.75LT), at LT, and at 25 and 75% of the difference between LT and peak (1.25LT, 1.75LT). Mean values for peak plasma epinephrine (Epi), plasma norepinephrine (NE), and serum GH concentrations were determined [Epi: 328 ± 93 (SE), 513 ± 76, 584 ± 109, 660 ± 72, and 2,614 ± 579 pmol/l; NE: 2.3 ± 0.2, 3.9 ± 0.4, 6.9 ± 1.0, 10.7 ± 1.6, and 23.9 ± 3.9 nmol/l; GH: 3.6 ± 1.5, 6.6 ± 2.0, 7.0 ± 2.0, 10.7 ± 2.4, and 13.7 ± 2.2 μg/l for 0.25, 0.75, 1.0, 1.25, and 1.75LT, respectively]. In all instances, the time of peak plasma Epi and NE preceded peak GH release. Plasma concentrations of Epi and NE always peaked at 20 min after the onset of Ex, whereas times to peak for GH were 54 ± 6 (SE), 44 ± 5, 38 ± 4, 38 ± 4, and 37 ± 2 min after the onset of Ex for 0.25–1.75LT, respectively. ANOVA revealed that intensity of exercise did not affect the foregoing time delay between peak NE or Epi and peak GH (range 17–24 min), with the exception of 0.25LT ( P < 0.05). Within-subject linear regression analysis disclosed that, with increasing exercise intensity, change in (Δ) GH was proportionate to both ΔNE ( P = 0.002) and ΔEpi ( P = 0.014). Furthermore, within-subject multiple-regression analysis indicated that the significant GH increment associated with an antecedent rise in NE ( P = 0.02) could not be explained by changes in Epi alone ( P = 0.77). Our results suggest that exercise intensity and GH release in the human may be coupled mechanistically by central adrenergic activation.

Phase I evaluation of a water-soluble etoposide prodrug, etoposide phosphate, given as a 5-minute infusion on days 1, 3, and 5 in patients with solid tumors.

1994 ◽  
Vol 12 (9) ◽  
pp. 1902-1909 ◽  
Author(s):  
D R Budman ◽  
L N Igwemezie ◽  
S Kaul ◽  
J Behr ◽  
S Lichtman ◽  
...  
Keyword(s):  
High Performance ◽  
Peak Plasma ◽  
Performance Status ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Water Soluble ◽  
High Dose ◽  
Maximum Plasma ◽  
Rapid Infusion ◽  
Etoposide Phosphate

PURPOSE To determine the toxicities, maximum-tolerated dose (MTD), and pharmacology of etoposide phosphate, a water-soluble etoposide derivative, administered as a 5-minute intravenous infusion on a schedule of days 1, 3, and 5 repeated every 21 days. PATIENTS AND METHODS Thirty-six solid tumor patients with a mean age of 63 years, performance status of 0 to 1, WBC count > or = 4,000/microL, and platelet count > or = 100,000/microL, with normal hepatic and renal function were studied. Doses evaluated in etoposide equivalents were 50, 75, 100, 125, 150, 175, and 200 mg/m2/d. Etoposide in plasma and urine and etoposide phosphate in plasma were measured by high-performance liquid chromatography (HPLC). Eleven of 36 patients were treated with concentrated etoposide phosphate at 150 mg/m2/d. RESULTS Grade I/II nausea, vomiting, alopecia, and fatigue were common. Leukopenia (mainly neutropenia) occurred at doses greater than 75 mg/m2, with the nadir occurring between days 15 and 19 posttreatment. All effects were reversible. Hypotension, bronchospasm, and allergic reactions were not observed in the first 25 patients. The MTD due to leukopenia was determined to be between 175 and 200 mg/m2/d. In 11 patients treated with concentrated etoposide phosphate, no local phlebitis was noted, but two patients did develop allergic phenomena. The conversion of etoposide phosphate to etoposide was not saturated in the dosages studied. Etoposide phosphate had peak plasma concentrations at 5 minutes, with a terminal half-life (t1/2) of 7 minutes. Etoposide reached peak concentrations at 7 to 8 minutes, with a t1/2 of 6 to 9 hours. Both etoposide phosphate and etoposide demonstrated dose-related linear increases in maximum plasma concentration (Cmax) and area under the curve (AUC). CONCLUSION Etoposide phosphate displays excellent patient tolerance in conventional dosages when administered as a 5-minute intravenous bolus. The suggested phase II dose is 150 mg/m2 on days 1, 3, and 5. The ability to administer etoposide phosphate as a concentrated, rapid infusion may prove of value both in the outpatient clinic and in high-dose regimens.

Investigating the causal link between a management improvement technique and organizational performance

2017 ◽  
Vol 40 (4) ◽  
pp. 429-450 ◽  
Author(s):  
André de Waal ◽  
Robert Goedegebuure
Keyword(s):  
Organizational Performance ◽  
High Performance ◽  
Management Practices ◽  
Longitudinal Research ◽  
Linear Regression Analysis ◽  
Causal Link ◽  
Content Type ◽  
Key Factor ◽  
Organizational Results ◽  
High Level

Purpose An important question in contemporary research is: do certain management practices cause better performance or do better performing organizations find it easier to adopt certain management practices? This question is also of importance when applying the high performance organization (HPO) framework, which is a scientifically validated technique designed to achieve and sustain a high level of performance. Many research studies correlate the HPO framework with improved organizational performance. There are, however, no studies which explicitly look at the causal relationship. This paper aims to provide empirical evidence of causality. Design/methodology/approach Longitudinal research was conducted at two companies. An HPO diagnosis was conducted at each company, after which management implemented the HPO framework. Two units at each company were selected as case studies. Data were collected, using a questionnaire and interviews, at the beginning and after 18 months, when the diagnoses were repeated. A linear regression analysis was performed to interpret the data. Findings Despite exposure to the same HPO framework techniques, organizational units achieved significantly different outcomes. In each company, one unit achieved a higher HPO score and higher organizational results, while the other unit had no change, or a lower HPO score and lower organizational results. The key factor was the manner in which unit managers applied the HPO framework. Practical implications Optimal effectiveness for the HPO framework occurs when management incorporates the HPO factors into the workplace and strives diligently to improve performance. Originality/value This research responds to the question “Do certain management practices cause better performance or do better performing organizations find it easier to adopt certain management practices?”

Pharmacokinetics of L-arginine during chronic administration to patients with hypercholesterolaemia

1999 ◽  
Vol 96 (2) ◽  
pp. 199-207 ◽  
Author(s):  
Oranee TANGPHAO ◽  
Stephan CHALON ◽  
Heitor MORENO ◽  
Brian B. HOFFMAN ◽  
Terrence F. BLASCHKE
Keyword(s):  
Nitric Oxide ◽  
Animal Studies ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Chronic Administration ◽  
Pharmacokinetic Studies ◽  
Acute Administration ◽  
Term Administration ◽  
Endothelial Nitric Oxide

Acute administration of L-arginine, the precursor of endothelial nitric oxide, has been shown to improve endothelial function in hypercholesterolaemic rabbits and humans. Animal studies suggest that this beneficial effect, which is thought to be related to the increased availability of nitric oxide, may not be sustained during chronic oral administration. Pharmacokinetic alterations may contribute to this observation. The present study was designed to examine the disposition of L-arginine in hypercholesterolaemic subjects during long-term administration. Plasma L-arginine concentrations were determined by HPLC in 10 patients (eight women and two men; mean age 46±16 years) after an intravenous dose of 10 or 30 g and an oral dose of 5 or 7 g. Pharmacokinetic studies were performed at regular intervals (4 weeks) during a 12-week period of oral L-arginine administration (14–21 g/day). The average plasma L-arginine concentrations before (baseline) and during administration were 16.1±1.2 and 22.5±1.3 μg/ml respectively (P< 0.05). Plasma concentrations of L-arginine remained above baseline throughout weeks 2–12. The L-arginine exposure, expressed as a normalized area-under-the-curve for 8 h (AUC0–8) after oral or intravenous doses during the first visit, was 894.4±118.7 and 1837.8±157.0 units respectively. There were no significant changes in peak plasma L-arginine concentrations or in the AUC0–8 after oral and intravenous doses during subsequent visits (P> 0.05). The mean non-renal clearance of L-arginine during the four visits remained constant. Knowledge of the pharmacokinetics of L-arginine may be useful in the design of clinical trials involving this agent, as well as in the interpretation of the pharmacodynamics of this important precursor of nitric oxide.

scholarly journals Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Owain Roberts ◽  
Saye Khoo ◽  
Andrew Owen ◽  
Marco Siccardi
Keyword(s):  
High Performance ◽  
Linear Regression Analysis ◽  
Intrinsic Clearance ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Content Type ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Dosing Regimens

ABSTRACT Treatment of HIV-infected patients coinfected with Mycobacterium tuberculosis is challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and antituberculosis (anti-TB) drugs. The aim of this study was to quantify the effect of cobicistat (COBI) or ritonavir (RTV) in modulating DDIs between darunavir (DRV) and rifampin (RIF) in a human hepatocyte-based in vitro model. Human primary hepatocyte cultures were incubated with RIF alone or in combination with either COBI or RTV for 3 days, followed by coincubation with DRV for 1 h. The resultant DRV concentrations were quantified by high-performance liquid chromatography with UV detection, and the apparent intrinsic clearance (CLint.app.) of DRV was calculated. Both RTV and COBI lowered the RIF-induced increases in CLint.app. in a concentration-dependent manner. Linear regression analysis showed that log10 RTV and log10 COBI concentrations were associated with the percent inhibition of RIF-induced elevations in DRV CLint.app., where β was equal to −234 (95% confidence interval [CI] = −275 to −193; P < 0.0001) and −73 (95% CI = −89 to −57; P < 0.0001), respectively. RTV was more effective in lowering 10 μM RIF-induced elevations in DRV CLint.app. (half-maximal [50%] inhibitory concentration [IC50] = 0.025 μM) than COBI (IC50 = 0.223 μM). Incubation of either RTV or COBI in combination with RIF was sufficient to overcome RIF-induced elevations in DRV CLint.app., with RTV being more potent than COBI. These data provide the first in vitro experimental insight into DDIs between RIF and COBI-boosted or RTV-boosted DRV and will be useful to inform physiologically based pharmacokinetic (PBPK) models to aid in optimizing dosing regimens for the treatment of patients coinfected with HIV and M. tuberculosis.

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