scholarly journals Modeling combinations of antiretroviral agents in vitro with integration of pharmacokinetics: guidance in regimen choice for clinical trial evaluation.

1996 ◽  
Vol 40 (5) ◽  
pp. 1143-1147 ◽  
Author(s):  
G L Drusano ◽  
M Prichard ◽  
P A Bilello ◽  
J A Bilello
Keyword(s):  
Drug Interaction ◽  
Steady State ◽  
Continuous Infusion ◽  
Three Dimensional ◽  
Pharmacokinetic Profile ◽  
Maximal Effect ◽  
Direct Evaluation ◽  
Average Percentage ◽  
The Mean

We propose a method for the selection of doses and dosing schedule for drugs to be used in combination. This approach uses the simulation of steady-state concentrations of the drugs in the combination and overlays these concentrations onto a three-dimensional effect surface. The MacSynergy II program is used to construct the three-dimensional drug interaction surface from the direct evaluation of drug combination effect in vitro. The study examined the combination of an inhibitor of the human immunodeficiency virus protease, A-77003, and the nucleoside analog zidovudine. Zidovudine concentrations from a steady-state interval were simulated on the basis of the administration of 100 mg every 12 h by mouth, while for A-77003 simulation profiles were for intravenous administration of 800 mg every 4 h as well as a continuous infusion of 200 mg/h. The average percentage of the maximal effect was taken as a measure of regimen effectiveness. Three different schedules of administration were examined. If both drugs were to be administered simultaneously, the model predicts a mean maximal effect of a steady-state interval (12 h) of 67%. If the drug doses were offset by 2 h, the mean maximal effect predicted was 71%. If A-77003 was to be given by continuous infusion, the mean maximal effect predicted was 90%. This method holds promise as a way of quickly evaluating potential combinations of agents that takes into account the drug interaction in a mathematically robust way and that allows the evaluation of the effect of each drug's pharmacokinetic profile.

scholarly journals Use of Drug Effect Interaction Modeling with Monte Carlo Simulation To Examine the Impact of Dosing Interval on the Projected Antiviral Activity of the Combination of Abacavir and Amprenavir

2000 ◽  
Vol 44 (6) ◽  
pp. 1655-1659 ◽  
Author(s):  
G. L. Drusano ◽  
D. Z. D'Argenio ◽  
S. L. Preston ◽  
C. Barone ◽  
W. Symonds ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Steady State ◽  
Protease Inhibitor ◽  
Antiviral Effect ◽  
In Vitro Assays ◽  
Maximal Effect ◽  
Dosing Interval ◽  
Average Percentage ◽  
The Impact

ABSTRACT The delineation of optimal regimens for combinations of agents is a difficult problem, in part because, to address it, one needs to (i) have effect relationships between the pathogen in question and the drugs in the combination, (ii) have knowledge of how the drugs interact (synergy, antagonism, and additivity), and (iii) address the issue of true between-patient variability in pharmacokinetics for the drugs in the population. We have developed an approach which employs a fully parametric assessment of drug interaction using the equation of W. R. Greco, G. Bravo, and J. C. Parsons (Pharmacol. Rev. 47:331–385, 1995) to generate an estimate of effects for the two drugs and have linked this approach to a population simulator, using Monte Carlo methods, which produce concentration-time profiles for the drugs in combination. This software automatically integrates the effect over a steady-state dosing interval and produces an estimate of the mean effect over a steady-state interval for each simulated subject. In this way, doses and schedules can be easily evaluated. This software allows for a rational choice of dose and schedule for evaluation in clinical trials. We evaluated different schedules of administration for the combination of the nucleoside analogue abacavir plus the human immunodeficiency virus type 1 protease inhibitor amprenavir. Amprenavir was simulated as either 800 mg every 8 h (q8h) or 1,200 mg q12h, each along with 300 mg q12h of abacavir. Both regimens produced excellent effects over the simulated population of 500 subjects, with average percentages of maximal effect (as determined from the in vitro assays) of 90.9% ± 11.4% and 80.9% ± 18.6%, respectively. This difference is statistically significant (P≪ 0.001). In addition, 68.8 and 46.0% of the population had an average percentage of maximal effect which was greater than or equal to 90% for the two regimens. We can conclude that the combination of abacavir plus amprenavir is a potent combination when it is given on either schedule. However, the more fractionated schedule for the protease inhibitor produced significantly better effects in combination. Clinicians need to explicitly balance the improvement in antiviral effect seen with the more fractionated regimen against the loss of compliance attendant to the use of such a regimen. This approach may be helpful in the preclinical evaluation of multidrug anti-infective regimens.

scholarly journals FILM SERI ANIMASI 3D BELAJAR BAHASA INDONESIA BERSAMA MADE SEBAGAI MEDIA PEMBELAJARAN BAHASA INDONESIA UNTUK PENUTUR ASING DI UNDIKSHA

2017 ◽  
Vol 6 (1) ◽  
pp. 20
Author(s):  
I Putu Andika Subagya Putra . ◽  
I Gede Mahendra Darmawiguna, S.Kom, M.Sc . ◽  
I Made Putrama, S.T., M.Tech. .
Keyword(s):  
Research And Development ◽  
Foreign Students ◽  
Three Dimensional ◽  
3D Animation ◽  
Average Percentage ◽  
Animated Film ◽  
The Mean ◽  
Film Series ◽  
Foreign Speakers ◽  
Bahasa Indonesia

Tujuan dari penelitian ini adalah untuk mengembangkan Film Seri Animasi 3d “Belajar Bahasa Indonesia Bersama Made” Sebagai Media Pembelajaran Bahasa Indonesia Untuk Penutur Asing Di Undiksha, agar mahasiswa asing yang tinggal atau berkunjung ke Indonesia dengan mudah dapat mempelajari Bahasa Indonesia. Metode penelitian yang digunakan dalam penelitian ini adalah Research and Development (R&D) dengan menggunakan model pengembangan ADDIE. Film animasi 3 dimensi ini dikembangkan dengan menggunakan software Blender dengan beberapa tahap pembuatan animasi, yaitu pra produksi, produksi, dan pasca produksi. Hasil dari penelitian ini, yaitu produk film animasi 3 dimensi berupa DVD dan respon dari peserta didik BIPA di Undiksha Singaraja terhadap Film Seri Animasi 3d “Belajar Bahasa Indonesia Bersama Made” Sebagai Media Pembelajaran Bahasa Indonesia Untuk Penutur Asing Di Undiksha yang terkategorikan sangat positif dengan rata-rata persentase 91,44%. Berdasarkan analisis dari 12 peserta didik BIPA diketahui 3 siswa memberikan respon yang sangat positif dan 9 siswa memberikan respon yang positif terhadap film animasi ini.Kata Kunci : BIPA, film Animasi, Animasi 3 Dimensi The purpose of this study is to develop a 3D Animation Film Series "Belajar Bahasa Indonesia Bersama Made" As an Indonesian Learning Media For Foreign Speakers In Undiksha, so that foreign students who stay or visit to Indonesia can easily learn Indonesian language. The method used in this research is the Research and Development (R & D) by using ADDIE development model. 3-D animated film is developed using software Blender with several stages of animation creation, are pre-production, production and post-production. The results of this study, three-dimensional animated film products such as DVD and the response of learners BIPA in Undiksha Singaraja to 3d Animation Film Series "Belajar Bahasa Indonesia Bersama Made" As an Indonesian Learning Media For Foreign Speakers In Undiksha are categorized very positively with the mean average percentage of 91,44%. Based on an analysis of 12 learners BIPA note 3 students gave a very positive response and 9 students responded positively to this animated film.keyword : BIPA, Animation Film, 3D Animation

The Comparative Pharmacodynamics of Remifentanil and Its Metabolite, GR90291, in a Rat Electroencephalographic Model 

1999 ◽  
Vol 90 (2) ◽  
pp. 535-544 ◽  
Author(s):  
Eugene H. Cox ◽  
Mariska W. E. Langemeijer ◽  
Josy M. Gubbens-Stibbe ◽  
Keith T. Muir ◽  
Meindert Danhof
Keyword(s):  
Steady State ◽  
Time Course ◽  
Parent Drug ◽  
Volume Of Distribution ◽  
Pharmacodynamic Model ◽  
Pharmacokinetic Parameters ◽  
Maximal Effect ◽  
Total Blood ◽  
The Mean

Background The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model. Methods Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood. Results Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 microg/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920+/-110 ml x min(-1) x kg(-1) and 1.00+/-0.93 l/kg for remifentanil and 15+/-2 ml x min(-1) x kg(-1) and 0.56+/-0.08 l/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25+/-5% and 0.30+/-0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal Emax pharmacodynamic model. The mean +/- SE values for the maximal effect (Emax), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109+/-12 microV, 9.4+/-0.9 ng/ml, and 2.2+/-0.3, respectively (n = 8). For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000+/-9,000 microg/ml and 2.5+/-0.4, respectively (n = 6). Conclusions Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration.

ANCD thrombectomy device: in vitro evaluation

2019 ◽  
Vol 12 (1) ◽  
pp. 77-81 ◽  
Author(s):  
Sonia Sanchez ◽  
Ignacio Cortiñas ◽  
Helena Villanova ◽  
Anna Rios ◽  
Iñaki Galve ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Treatment Strategies ◽  
Local Flow ◽  
Guide Catheter ◽  
First Pass ◽  
Thrombectomy Device ◽  
The Mean ◽  
Three Dimensional Models ◽  
Number Of Passes

IntroductionEndovascular treatment of stroke, although highly effective, may fail to reach complete recanalization in around 20% of cases. The Advanced Thrombectomy System (ANCD) is a novel stroke thrombectomy device designed to reduce clot fragmentation and facilitate retrieval by inducing local flow arrest and allowing distal aspiration in combination with a stent retriever. We aimed to assess the preclinical efficacy of ANCD.MethodsSoft red blood cell (RBC)-rich (n=20/group) and sticky fibrin-rich (n=30/group) clots were used to create middle cerebral artery (MCA) occlusions in two vascular phantoms. Three different treatment strategies were tested: (1) balloon guide catheter + Solitaire (BGC+SR); (2) distal access catheter + SR (DAC+SR); and (3) ANCD+SR, until complete recanalization was achieved or to a maximum of three passes. The recanalization rate was determined after each pass.ResultsAfter one pass, ANCD+SR resulted in an increased recanalization rate (94%) for all clots together compared with BGC+SR (66%; p<0.01) or DAC+SR (80%; p=0.04). After the final pass the recanalization rate increased in all three groups but remained higher with ANCD+SR (100%) than with BGC+SR (74%; p<0.01) or DAC+SR (90%; p=0.02). The mean number of passes was lower with ANCD+SR (1.06) than with BGC+SR (1.46) or DAC+SR (1.25) (p=0.01). A logistic regression model adjusted for treatment arm, clot type, and model used showed that both RBC-rich clots (OR 8.1, 95% CI 1.6 to 13.5) and ANCD+SR (OR 3.9, 95% CI 1.01 to 15.8) were independent predictors of first-pass recanalization.ConclusionIn in vitro three-dimensional models replicating MCA-M1 occlusion, ANCD+SR showed significantly better recanalization rates in fewer passes than other commonly used combinations of devices.

scholarly journals In Vitro Interactions of Artemisinin with Atovaquone, Quinine, and Mefloquine against Plasmodium falciparum

2002 ◽  
Vol 46 (5) ◽  
pp. 1510-1515 ◽  
Author(s):  
S. Gupta ◽  
M. M. Thapar ◽  
W. H. Wernsdorfer ◽  
A. Björkman
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Interaction ◽  
In Vitro Culture ◽  
Effective Concentration ◽  
Interstrain Differences ◽  
Molar Ratios ◽  
The Mean ◽  
In Vitro Interactions

ABSTRACT The interactions of artemisinin with atovaquone, quinine, and mefloquine were investigated in three Plasmodium falciparum strains (strains F-32, FCR-3, and K-1) by an in vitro culture assay. The parasites were cultured for 48 h in the presence of different concentrations and proportions of two drugs at a time in a checkerboard design. The response parameters were determined, and the sums of the fractional inhibitory concentrations (ΣFICs) of the drug combinations were calculated for different degrees of inhibition (50% effective concentration [EC50], EC90, and EC99). Within therapeutically relevant molar ratios (19 to 200), the combination of quinine and artemisinin showed mean ΣFICs of 1.71 at the EC50, 0.36 at the EC90, and 0.13 at the EC99, indicating increasing synergism. Within the range of molar ratios of 4.3 to 50, the combination of mefloquine and artemisinin yielded mean ΣFCIs of 0.93, 0.44, and 0.31 at the EC50, EC90, and EC99, respectively, indicating synergism. The atovaquone combination showed additive activity to synergism at atovaquone/artemisinin proportions considered relevant to the in vivo situation, i.e., between 4.3 and 200, with the mean ΣFICs decreasing from 1.34 at the EC50 to 0.85 and 0.23 at the EC90 and EC99, respectively. Interstrain differences in the degree of drug interaction were seen with the three strains for all combinations. Synergism was most consistent with quinine.

Phase I Assessment of the Pharmacokinetics, Metabolism, and Safety of Emitefur in Patients With Refractory Solid Tumors

2000 ◽  
Vol 18 (19) ◽  
pp. 3423-3434 ◽  
Author(s):  
J. Nemunaitis ◽  
R. Eager ◽  
T. Twaddell ◽  
A. Corey ◽  
K. Sekar ◽  
...  
Keyword(s):  
Steady State ◽  
Phase I ◽  
Solid Tumors ◽  
Prolonged Exposure ◽  
Circadian Variation ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Minimum Effective Concentration ◽  
Grade 3

PURPOSE: To determine the toxicities, dose-limiting toxicities (DLT), maximum-tolerated dose, and pharmacokinetic profile of emitefur (BOF-A2) in patients with advanced solid tumors. METHODS: This was a phase I dose-escalating trial in which cohorts of patients received BOF-A2 (cohort 1, 300 mg/m2 orally [PO] tid; cohort 2, 200 mg/m2 PO tid; cohort 3, 200 mg/m2 bid; and cohort 4, 250 mg/m2 bid) for 14 consecutive days followed by 1 week of rest (cycle 1). Pharmacokinetics, toxicity, and tumor response were monitored. RESULTS: Nineteen patients received 110 cycles (three patients in cohort 1, three patients in cohort 2, 10 patients in cohort 3, and three patients in cohort 4). DLT (grade 3 stomatitis, diarrhea, leukopenia) was observed in cohorts 1, 2, and 4. Pharmacokinetics indicated that prolonged systemic expression of fluorouracil (5-FU) is maintained after administration of BOF-A2 at a dose of 200 mg bid for 14 days. The mean steady-state concentration of plasma 5-FU was ≥ 24 ng/mL, which was 184-fold greater than the minimum effective cytotoxic concentration in vitro. Lack of variation of 5-FU trough levels within a day at steady-state indicates suppression of circadian variation. One patient in cohort 3 achieved a partial response and five patients maintained stable disease in excess of 6 months. CONCLUSION: BOF-A2 at a dose of 200 mg PO bid for 14 days followed by 7 days of rest is well tolerated. Prolonged exposure to 5-FU above the predicted preclinical minimum effective concentration is maintained, without evidence of circadian variation. Furthermore, evidence of antitumor activity is suggested.

scholarly journals Some Physiological Factors Affecting the Binding of Cortisol by Human Plasma Proteins

1977 ◽  
Vol 14 (1-6) ◽  
pp. 35-38 ◽  
Author(s):  
J. D. Few ◽  
J. R. Haspineall
Keyword(s):  
Steady State ◽  
Human Plasma ◽  
Plasma Proteins ◽  
Gel Filtration ◽  
Physiological Factors ◽  
Mean Values ◽  
Factors Affecting ◽  
Free Cortisol ◽  
The Mean

Steady-state gel filtration has been used to study the binding of cortisol to human plasma proteins in vitro. Raising the temperature from 37°C to 41°C results in the mean proportion of free (non-protein-bound) cortisol rising approximately from 7% to 11%. Addition of cortisol to plasma ≡ 275 nmol/l) also increased the proportion of free cortisol by approximately 50%. Cortisone is less strongly bound to plasma proteins than cortisol. The mean values (±S.D.) for five samples were free cortisol 8.4 ± 1.1% and free cortisone 26.0±3.8%.

Heat Transfer Normal to Paired Arterioles and Venules Embedded in Perfused Tissue During Hyperthermia

1988 ◽  
Vol 110 (4) ◽  
pp. 277-282 ◽  
Author(s):  
C. K. Charny ◽  
R. L. Levin
Keyword(s):  
Heat Transfer ◽  
Steady State ◽  
Three Dimensional ◽  
Numerical Data ◽  
Tissue Temperature ◽  
Three Dimensional Model ◽  
Sources And Sinks ◽  
The Mean ◽  
Krogh Cylinder ◽  
Subsequent Incorporation

A numerical model of the heat transer normal to an arteriole-venule pair embedded in muscle tissue has been constructed. Anatomical data describing the blood vessel size, spacing, and density have been incorporated into the model. This model computes temperatures along the vessel walls as well as the temperature throughout the tissue which comprises an infinitely long Krogh cylinder around the vessel pair. Tissue temperatures were computed in the steady-state under resting conditions, while transient calculations were made under hyperthermic conditions. Results show that for both large- (1st generation) and medium-sized (5th generation) vessel pairs, the mean tissue temperature within the tissue cylinder is not equal to the mean of the arteriole and venule blood temperatures under both steady-state and transient conditions. The numerical data were reduced so that a comparison could be made with the predictions of a simple two-dimensional superposition of line sources and sinks presented by Baish et al. [1]. This comparison reveals that the superposition model accurately describes the heat transfer effects during hyperthermia, permitting subsequent incorporation of this theory into a realistic three-dimensional model of heat transfer in a whole limb during hyperthermia.

Ex vivo zidovudine (AZT) treatment of CD34+ bone marrow progenitors causes decreased steady state mitochondrial DNA (mtDNA) and increased lactate production

2004 ◽  
Vol 23 (4) ◽  
pp. 173-185 ◽  
Author(s):  
L D Lewis ◽  
S Amin ◽  
C I Civin ◽  
P S Lietman
Keyword(s):  
Bone Marrow ◽  
Mitochondrial Dna ◽  
Steady State ◽  
Nuclear Dna ◽  
Ex Vivo ◽  
Lactate Production ◽  
Nuclear Dna Content ◽  
Content Ratio ◽  
The Mean

Haematopoietic suppression is one of the dose-limiting side effects of chronic zidovudine (AZT) therapy. We tested the hypothesis that AZT would reduce mitochondrial DNA (mtDNA) content in haematopoietic progenitors causing impaired haematopoiesis and mitochondrial dysfunction. We studied the effects of AZT 0 / 50 M in vitro, on normal human CD34 / haematopoietic progenitor cells cultured ex vivo for up to 12 days. The mean AZT IC50 for granulocyte (phenotype CD15 / /CD14 /) and erythroid (phenotype glycophorin / /CD45 /) cell proliferation was 2.5 M (SD9 / 0.7) and 0.023 M (SD9 / 0.005), respectively. In myeloid-rich cell cultures, the mean lactate content of the media, compared to untreated controls, increased by 86% (SD9 / 23) at 10 M AZT and in erythroid-rich cultures it increased by 134% (SD9 / 24) in the presence of 0.5 M AZT. In myeloid-rich cultures the AZT IC50 for the reduction in the mitochondrial/nuclear DNA content ratio was 5.6 M, whereas in erythroid rich cultures this AZT IC50 was B / 0.0005 M. AZT produced concentration-dependent inhibition of CD34 / progenitor proliferation into both myeloid and erythroid lineages; erythropoiesis was more sensitive than myelopoiesis. Concurrently, AZT reduced steady state mtDNA content, while increasing lactate production. These findings support the hypothesis that mtDNA is one of the intracellular targets involved in the pathogenesis of AZT-associated bone marrow progenitor cell toxicity.

scholarly journals Pharmacokinetics of Solithromycin (CEM-101) after Single or Multiple Oral Doses and Effects of Food on Single-Dose Bioavailability in Healthy Adult Subjects

2011 ◽  
Vol 55 (5) ◽  
pp. 1997-2003 ◽  
Author(s):  
J. Gordon Still ◽  
Jennifer Schranz ◽  
Thorsten P. Degenhardt ◽  
Drusilla Scott ◽  
Prabhavathi Fernandes ◽  
...  
Keyword(s):  
Phase 1 ◽  
Pharmacokinetic Profile ◽  
Time Curve ◽  
Time To Peak ◽  
Dose Study ◽  
Human Pharmacokinetic ◽  
The Mean ◽  
Double Blinded ◽  
Oral Doses

ABSTRACTThe pharmacokinetics of orally administered solithromycin (CEM-101), a novel fluoroketolide, were evaluated in healthy subjects in three phase 1 studies. In two randomized, double-blinded, placebo-controlled studies, escalating single oral doses of solithromycin (50 to 1,600 mg) or seven oral daily doses (200 to 600 mg) of solithromycin were administered. A third study evaluated the effects of food on the bioavailability of single oral doses (400 mg) of solithromycin. Following single doses, the median time to peak concentration (Tmax) ranged from 1.5 h to 6 h. The mean maximum measured plasma concentration (Cmax) ranged from 0.0223 μg/ml to 19.647 μg/ml, and the area under the concentration-versus-time curve from time zero to timet(AUC0–t) ranged from 0.0402 μg · h/ml to 28.599 μg · h/ml. There was no effect of high-fat food on the oral bioavailability of solithromycin. In the multiple-dose study, after 7 days, the mean maximum measured plasma solithromycin concentration at steady-state (Cmax,ss) ranged from 0.248 to 1.50 μg/ml, and the area under the concentration-versus-time curve over the final dosing interval (AUCτ) ranged from 2.310 to 18.41 μg · h/ml. These values indicate a greater than proportional increase in exposure at 200 and 400 mg but a proportional exposure at 600 mg. MedianTmaxvalues remained constant between day 1 and day 7. Moderate accumulation ratios of solithromycin were observed after 7 days of dosing. All dose regimens of solithromycin were well tolerated, and no discontinuations due to an adverse event occurred. The human pharmacokinetic profile and tolerability of solithromycin, combined with itsin vitropotency and efficacy in animal models against a broad spectrum of pathogens, support further development of solithromycin.

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