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Biomedical subjects

D W Miller

Publications and source records attributed to D W Miller.

At least 37 records · Page 2Linked to original sources
PubMed2001

Transport of fluorescein in MDCKII-MRP1 transfected cells and mrp1-knockout mice.

The multidrug resistant-associated protein 1 (MRP1) is a membrane-bound transport protein that is involved in the efflux of organic anions and has been implicated in multidrug resistance in cancer. MRP1 has also been reported to be ubiquitously expressed in normal tissues, including the brain. The presence of functional organic anion transporters in the blood-brain and blood-CSF barriers that influence the distribution of various compounds to the brain has long been known. The purpose of this study was to examine the role of MRP1 in the brain distribution of a model organic anion, fluorescein. The substrate specificity of MRP1 for fluorescein was initially determined by examining the accumulation of fluorescein in MDCKII MRP1-transfected cells. The distribution of fluorescein in the brain was then examined in wild-type and mrp1 gene knockout mice. The results show that in MDCKII MRP1-transfected cells, the accumulation of fluorescein was significantly lower (about 40% lower) than that in wild-type MDCKII cells. MRP1 inhibitors such as probenecid, MK-571, and LY402913 enhanced fluorescein accumulation in MDCKII MRP1-transfected cells to a greater extent than in wild-type MDCKII cells. In an in vivo study, after intravenous injection of fluorescein, the fluorescein brain-to-plasma concentration ratio in mrp1 knockout mice was not significantly different than that in wild-type mice. However, when probenecid was co-administered with fluorescein in wild-type mice, the fluorescein brain-to-plasma ratio was significantly increased (1.5-fold). These findings suggest that fluorescein is a substrate for MRP1. Furthermore, the in vivo study also suggests that MRP1 has a limited role in the transport and distribution of fluorescein in the brain. Therefore, other organic anion transport proteins, including the various isoforms of the MRP family, may be responsible for the accumulation and transport of organic anions in the brain.

ATP-Binding Cassette Transporters↗
PubMed2001

Methodologies and tools for proton beam design for lung tumors.

PURPOSE: Proton beams can potentially increase the dose delivered to lung tumors without increasing the dose to critical normal tissues because protons can be stopped before encountering the normal tissues. This potential can only be realized if tissue motion and planning uncertainties are correctly included during planning. This study evaluated several planning strategies to determine which method best provides adequate tumor coverage, minimal normal tissue irradiation, and simplicity of use. METHODS AND MATERIALS: Proton beam treatment plans were generated using one or more of three different planning strategies. These strategies included designing apertures and boluses to the PTV, apertures to the PTV and boluses to the CTV, and aperture and bolus to the CTV. RESULTS: The planning target volume as specified in ICRU Report 50 can be used only to design the lateral margins of beams, because the distal and proximal margins resulting from CT number uncertainty, beam range uncertainty, tissue motions, and setup uncertainties, are different than the lateral margins resulting from these same factors. The best strategy for target coverage with the planning tools available overirradiated some normal tissues unnecessarily. The available tools also made the planning of lung tumors difficult. CONCLUSIONS: This study demonstrated that inclusion of target motion and setup uncertainties into a plan should be performed in the beam design step instead of creating new targets. New computerized treatment planning system tools suggested by this study will ease planning, facilitate abandonment of the PTV concept, improve conformance of the dose distribution to the target, and improve conformal avoidance of critical normal tissues.

Algorithms↗
PubMed2001

The use of transgenic mice in pharmacokinetic and pharmacodynamic studies.

Transgenic technology has made it possible to alter the genetic make-up of a laboratory mouse through the removal or insertion of selected genes. The resulting transgenic mouse provides a means for determining the developmental and functional contributions of selected genes and the proteins they encode. The current article reviews examples of the use of transgenic mice in pharmacokinetic and pharmacodynamic studies. In addition to examining current applications of transgenic technology in the areas of pharmacokinetics and pharmacodynamics, the potential for future advancements as well as limitations of the technology are discussed.

Animals↗
PubMed2001

Evaluation of creatine transport using Caco-2 monolayers as an in vitro model for intestinal absorption.

Creatine is a nutraceutical that has gained popularity in both well-trained and casual athletes for its performance-enhancing or ergogenic properties. The major disadvantages of creatine monohydrate formulations are poor solubility and oral bioavailability. In the present study, creatine transport was examined using Caco-2 monolayers as an in vitro model for intestinal absorption. Confluent monolayers of Caco-2 cells (passage 25-35) were used for the permeability studies. Monolayers were placed in side-by-side diffusion chambers. (14)C-Creatine (0.1-0.5 microCi/mL) was added to either the apical or basolateral side, and the transport of the creatine across the Caco-2 monolayer was measured over a 90-min period. The apical to basolateral transport of (14)C-creatine was small, ranging from 0.2-3% of the original amount appearing on the receiver side in a 90-min period. Interestingly, the basolateral to apical permeability of radiolabeled creatine was substantially greater than that observed in the apical to basolateral direction. Studies with drug efflux transport inhibitors indicate that neither the P-glycoprotein nor multidrug resistance-associated protein is involved in the enhanced basolateral to apical transport of creatine.

Biological Transport, Active↗
PubMed2001

Conformal proton radiation treatment for retroperitoneal neuroblastoma: introduction of a novel technique.

BACKGROUND: Postoperative irradiation for locoregionally advanced neuroblastoma requires coverage of the paraspinal retroperitoneum. The proximity of both kidneys and the liver, and a more complex target configuration, can pose a dosimetric challenge for conventional X-ray treatment and intraoperative irradiation. We utilized proton radiation therapy (PRT) to reduce dose to uninvolved kidneys, liver, intestine, and spinal cord. PROCEDURE: A 4-year-old male underwent PRT for neuroblastoma of the right adrenal gland, following chemotherapy and delayed surgical resection. Clinical target volume (CTV), boost volume, and normal structures were outlined on the 3D treatment planning CT scan. The patient received 25.2 CGE (cobalt Gray equivalent) to the CTV and 34.2 CGE to the boost region, using 1.8 CGE per fraction, five treatments per week. Dose-volume histograms (DVHs) were obtained for target and nontarget structures. RESULTS: The 95% isodose volume enclosed CTV and boost volumes. The dose to 50% of the ipsilateral kidney, with tumor involvement of the medial renal surface, was < or = 16 CGE (47% of prescribed total dose). Doses to 50% and 20% of the contralateral kidney in close proximity to deep left-side, paraspinal soft tissue involvement were restricted to 1 CGE and 10 CGE, respectively. Eighty percent of the liver received 27 CGE (80% of prescribed dose). Using a patch technique, unique to charged particle therapy, the spinal cord was almost completely spared during boost volume irradiation. CONCLUSIONS: PRT can achieve excellent dose conformity for advanced retroperitoneal, paraspinal lesions, while respecting normal tissue tolerance levels.

Child, Preschool↗
PubMed2001

Targeting of adenovirus to endothelial cells by a bispecific single-chain diabody directed against the adenovirus fiber knob domain and human endoglin (CD105).

The use of adenoviruses for antivascular cancer gene therapy is limited by their low transduction efficiency for endothelial cells. We have developed a recombinant bispecific antibody as a molecular bridge, linking the adenovirus capsid to the endothelial cell surface protein endoglin, for vascular targeting of adenoviruses. Endoglin (CD105), a component of the transforming growth factor beta receptor complex, represents a promising target for antivascular cancer therapy. Endoglin is expressed predominantly on endothelial cells and is upregulated in angiogenic areas of tumors. We isolated single-chain Fv fragments directed against human endoglin from a human semisynthetic antibody library. One of the isolated scFv fragments (scFv C4) bound specifically to various proliferating primary endothelial cells or cell lines including HUVEC, HDMEC, HMVEC, and HMEC. ScFv C4 was therefore used to construct a bispecific single-chain diabody directed against endoglin and the adenovirus fiber knob domain (scDb EDG-Ad). This bispecific molecule mediated enhanced and selective adenovirus transduction of HUVECs, which was independent from binding to the coxsackievirus and adenovirus receptor (CAR) and alpha(v)-integrins. Thus, adenovirus infection was redirected to a new cellular receptor (CD105) and cell entry pathway. These results demonstrate the utility of bispecific single-chain diabodies, which can be produced in large quantities in bacteria, for the retargeting of adenoviruses in cancer gene therapy.

Adenoviridae↗
PubMed2001

Effect of probenecid on fluorescein transport in the central nervous system using in vitro and in vivo models.

PURPOSE: The purpose of this study was to characterize the function of multidrug resistance-associated proteins (MRPs) (or MRP-like organic anion transport systems) in the blood-brain harrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) using both an in vitro BBB model and an in vivo microdialysis model. METHODS: In vitro functional studies were performed using bovine brain microvessel endothelial cells (BBMEC). The accumulation of fluorescein, an anionic fluorescent dye, in BBMEC was determined with and without the presence of inhibitors of various efflux transport proteins. In vivo microdialysis simultaneously monitored fluorescein concentrations in cortical extracellular fluid and cerebrospinal fluid. The effect of probenecid on the in vivo distribution of fluorescein was studied using a balanced crossover design in the rat. RESULTS: In vitro experiments showed that probenecid, indomethacin, LY-329146, and all MRP inhibitors significantly increased (two- to threefold) the accumulation of fluorescein in BBMEC, whereas LY-335979, a P-gp inhibitor, had no effect on the accumulation of fluorescein. Probenecid significantly increased fluorescein plasma concentration and the plasma free fraction in vivo. The distribution of fluorescein across the BBB and BCSFB was enhanced by 2.2- and 1.9-fold, respectively, when probenecid was coadministered, even after correction for increased fluorescein plasma concentrations and free fraction. CONCLUSIONS: These results demonstrate that MRPs or MRP-like transport system(s) may play an important role in fluorescein distribution across both BBB and BCSFB. This study showed that microdialysis proved to be a powerful in vivo technique for the study of transport systems in the central nervous system, and in vitro/in vivo correlations are possible using these model systems.

Algorithms↗
PubMed2001

Pluronic P85 enhances the delivery of digoxin to the brain: in vitro and in vivo studies.

Drug delivery across the blood-brain barrier is limited by several mechanisms. One important mechanism is drug efflux, mediated by several transport proteins, including P-glycoprotein. The goal of this work was to examine the effect of a novel drug delivery system, Pluronic block copolymer P85, on P-glycoprotein-mediated efflux from the brain using in vitro and in vivo methods. The hypothesis was that specific Pluronic copolymer systems enhance drug delivery to the central nervous system through the inhibition of P-glycoprotein. The effect of P85 on the cellular accumulation and transport of digoxin, a model P-glycoprotein substrate, was examined in porcine kidney epithelial cells (LLC-PK1) transfected with the human MDR1 gene. The effect of P85 on the directional flux across an in vitro BBB was also characterized. In vivo brain distribution studies were accomplished using wild-type and P-glycoprotein knockout mice. Pluronic increased the cellular accumulation of digoxin 3-fold in LLC-PK1 cells and 5-fold in the LLC-PK1-MDR1-transfected cells. Similar effects were observed for a prototypical P-glycoprotein substrate rhodamine-123. P85 treatment decreased the basolateral-to-apical and increased the apical-to-basolateral digoxin flux across LLC-PK1-MDR1 cell monolayers, and analogous results were observed with the in vitro BBB monolayers. The coadministration of 1% P85 with radiolabeled digoxin in wild-type mice increased the brain penetration of digoxin 3-fold and the digoxin level in the P85-treated wild-type mice was similar to that observed in the P-glycoprotein-deficient animals. These data indicate that Pluronic P85 can enhance the delivery of digoxin to the brain through the inhibition of the P-glycoprotein-mediated efflux mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Tumor necrosis factor-alpha induces cyclooxygenase-2 expression and prostaglandin release in brain microvessel endothelial cells.

Primary cultured bovine brain microvessel endothelial cells (BBMECs), were used as an in vitro model of the blood-brain barrier to examine the involvement of eicosanoids in the permeability and cytoskeletal structural changes observed following exposure to tumor necrosis factor-alpha (TNF-alpha). Compared with control monolayers, BBMECs exposed to TNF-alpha formed actin filament tangles and extracellular gaps with a resultant increase in permeability. Both the permeability and cytoskeletal changes observed with TNF-alpha were significantly reduced following pretreatment with NS-398 or indomethacin, inhibitors of cyclooxygenase (COX). Western blot analysis showed that TNF-alpha had no apparent effect on the expression of COX-1, but did induce the expression of COX-2 in the BBMECs. The induction of COX-2 expression occurred within the same time frame (2-4 h following TNF-alpha exposure) as the permeability increases observed with the cytokine. Consistent with the increased expression of COX-2, BBMEC monolayers exposed to TNF-alpha had significantly greater secretion and release of prostaglandin E(2) (PGE(2)) and prostaglandin F(2alpha) (PGF(2alpha)). Furthermore, BBMEC monolayers treated with PGE(2) or PGF(2alpha) showed significant increases in permeability and cytoskeletal structural changes when compared with control monolayers. Together, these results suggest that the TNF-alpha-induced permeability and cytoskeletal structural effects are due, in part, to an induction of the COX-2 system and increased release of prostaglandins in the cerebral microvasculature.

Animals↗
PubMed2001

Economic evaluation of lamivudine compared with interferon-alpha in the treatment of chronic hepatitis B in the United States.

OBJECTIVE: To determine whether lamivudine or interferon-alpha (IFN-alpha) is the more successful treatment for chronic hepatitis B given a fixed drug budget. STUDY DESIGN: A decision-tree model of 1 year. PATIENTS AND METHODS: Average wholesale prices were used to estimate drug costs. A fixed drug budget of $558,910, sufficient to treat 100 patients with IFN-alpha, was assumed. Clinical data were taken from randomized controlled trials. The outcome measures used were hepatitis B "e" antigen (HBeAg) seroconversion rates and rates of progression to cirrhosis. RESULTS: The analysis showed that given the fixed drug budget, 353 patients could be treated with lamivudine, resulting in an expected 62 HBeAg seroconversions, with 6 patients progressing to cirrhosis. Given the same drug budget, 100 patients could be treated with IFN-alpha, leaving 253 patients untreated. This treatment scenario would result in an expected 32 HBeAg seroconversions, with 28 patients progressing to cirrhosis. Compared with no treatment, the costs per additional HBeAg seroconversion obtained were $12,703 for lamivudine and $39,922 for IFN-alpha. In addition, each case of cirrhosis avoided through lamivudine treatment resulted in significant annual cost savings. Lamivudine therapy also provided additional clinical benefits (e.g., normalization of alanine transaminase levels, reduction in hepatitis B virus DNA levels, improvement in liver histology) to patients who do not seroconvert. CONCLUSION: From the perspective of a third-party payer with a fixed drug budget, lamivudine is more cost-effective therapy than IFN-alpha for the treatment of chronic hepatitis B.

Antiviral Agents↗
PubMed2001

Mechanism of pluronic effect on P-glycoprotein efflux system in blood-brain barrier: contributions of energy depletion and membrane fluidization.

Pluronic block copolymer, P85, inhibits the P-glycoprotein (Pgp) drug efflux system and increases the permeability of a broad spectrum of drugs in the blood-brain barrier (BBB). This study examines the mechanisms by which P85 inhibits Pgp using bovine brain microvessel endothelial cells (BBMEC) as an in vitro model of the BBB. The hypothesis was that simultaneous alterations in intracellular ATP levels and membrane fluidization in BBMEC monolayers by P85 results in inhibition of the drug efflux system. The methods included the use of 1) standard Pgp substrate rhodamine 123 to assay the Pgp efflux system in BBMEC, 2) luciferin/luciferase assay for ATP intracellular levels, and 3) 1,6-diphenyl-1,3,5-hexatriene for membrane microviscosity. Using 3H-labeled P85 and fluorescein-labeled P85 for confocal microscopy, this study suggests that P85 accumulates in the cells and intracellular organelles such as the mitochondria where it can interfere with metabolic processes. Following exposure of BBMEC to P85, the ATP levels were depleted, and microviscosity of the cell membranes was decreased. Furthermore, P85 treatment decreased Pgp ATPase activity in membranes expressing human Pgp. A combination of experiments examining the kinetics, concentration dependence, and directionality of P85 effects on Pgp-mediated efflux in BBMEC monolayers suggests that both energy depletion (decreasing ATP pool available for Pgp) and membrane fluidization (inhibiting Pgp ATPase activity) are critical factors contributing to the activity of the block copolymer in the BBB.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Effect of maternal undernutrition during pregnancy on early ovarian development and subsequent follicular development in sheep fetuses.

Gonad development in female sheep fetuses is thought to occur in a number of key stages. The aim of this study was to determine the effects of maternal undernutrition, applied at one or more of these critical stages, on fetal ovarian development. Groups of ewes (n = 11-19) were fed rations providing either 100% (high; H) or 50% (low; L) of energy requirements for live weight maintenance during selected 'windows' during gestation. Control ewes (HH and HHH) were fed the H ration from mating until they were killed at days 50, 65 (HH) or 110 (HHH) of gestation, whereas ewes of other groups were fed the L ration for the periods between day 0 and day 30 of gestation (LH and LHH), day 31 and day 50 or 65 of gestation (HL and HLH), day 65 and day 110 of gestation (HHL) or day 0 of gestation until the animals were killed (LL and LLL). At day 50 of gestation, there was no effect of nutritional treatment on mean fetal mass but compared with HH animals, mean fetal ovarian mass was significantly lower in HL (P < 0.05) and LL (P < 0.001) animals. At day 65 of gestation, there were significantly fewer germ cells (P < 0.05) at the resting, diplotene stage of initial meiosis in LL animals than there were in HH animals, indicating delayed germ cell maturation and onset of meiosis. Qualitative assessment of proliferative cell nuclear antigen immunostaining indicated that, at day 50 of gestation, staining was located predominantly in the germ cells, whereas by day 65 of gestation, staining was confined predominantly to somatic cells. Undernutrition in each one of these windows was associated with delayed ovarian follicular development (P < 0.05-0.001) as measured by development of the granulosa cell layer at day 110 of gestation. This study demonstrates that undernutrition before and during folliculogenesis can delay fetal follicular development.

Analysis of Variance↗
PubMed2000

Normal tissue complication probability (NTCP) calculations as a means to compare proton and photon plans and evaluation of clinical appropriateness of calculated values.

Calculation of normal tissue complication probabilities (NTCP) for proton radiation therapy (PRT) and two photon radiation therapy techniques for cranial irradiation of childhood optic nerve gliomas was made. Evaluation of usefulness of calculated NTCP values for comparison of treatment plans and clinical appropriateness of computed data was used. Three radiation plans were calculated on datasets of children treated previously for optic nerve gliomas with PRT. Dose-volume histograms (DVH) were computed and used to calculate NTCP. Evaluated complication endpoints were necrosis, blindness, and cognitive impairment. Calculated NTCP depended strongly on tumor volume and the normal tissue volume exposed to high radiation doses. Dose conformity and steeper dose-gradient correlated with reduced NTCP. Regarding the chosen complication endpoints, PRT was superior to 3D photons; conventional photons were calculated to have the highest NTCPs. Differences might reach clinical significance for cognitive impairment, a frequently observed toxicity. Calculated NTCP values were highly dependent on implemented clinical data. Calculation of NTCP can be used for ranking of treatment plans and modalities. Highly dependent on implemented clinical data, the calculated percentage of NTCP might be more of a figure of merit than a real predictive value and requires comparison to clinical experience. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 351-358 (2000).

Child↗
PubMed2000

(13)C NMR and electron ionization mass spectrometric data-activity relationship model of estrogen receptor binding.

Two Spectroscopic Data-Activity Relationship (SDAR) models based on (13)C nuclear magnetic resonance (NMR) and electron ionization mass spectra (EI MS) data were developed for 108 compounds whose relative binding affinities (RBA) to the estrogen receptor are known. The (13)C NMR and EI MS data were used as spectrometric digital fingerprints to reflect the electronic and structural characteristics of the compounds. Both SDAR models segregated the 108 compounds into 20 strong, 15 medium, and 73 weak relative binding classifications. The first SDAR model, based on (13)C NMR data alone, gave a leave-one-out (LOO) cross-validation of 75.0%. The second SDAR model, based on a composite of (13)C NMR and EI MS data, gave a LOO cross-validation of 82.4%. Many of the misidentifications from the cross-validations were between medium and weak classifications, where there were fewer specific spectrometric characteristics to identify the relationship of spectra to estrogen receptor binding. Real and predicted (13)C NMR chemical shifts were used to test the predictive behavior of both SDAR models. The ease of use and speed of SDAR modeling may facilitate their use with other toxicological endpoints.

Carbon Radioisotopes↗
PubMed2000

Conformal proton radiation therapy of the posterior fossa: a study comparing protons with three-dimensional planned photons in limiting dose to auditory structures.

PURPOSE: Conventional radiation therapy for pediatric posterior fossa tumors can cause sequelae such as hearing loss and impairments in language and learning. Modern three-dimensional (3D) treatment techniques have improved dose conformity to the posterior fossa. This report compares the normal tissue dose-sparing capabilities of proton radiation therapy (PRT) with 3D conformal photon plans. METHODS AND MATERIALS: Nine children underwent previous PRT for primary CNS malignancies. Using original planning CT scans, the posterior fossa, inner and middle ear, and temporal lobes were delineated. Three-dimensional treatment plans were generated for protons and photons. Normal tissue exposures were calculated by averaging mean doses received and by analysis of dose-volume histogram. RESULTS: The 95% isodose encompassed the posterior fossa in all plans. Normal structures received markedly less radiation from PRT plans than from 3D photon plans. The cochlea received an average mean of 25 +/- 4% of the prescribed dose from PRT, and 75 +/- 6% from photons. Forty percent of temporal lobe volume was completely excluded using protons; with photons 90% of the temporal lobe received 31% of the dose. CONCLUSION: PRT resulted in increased dose sparing of normal structures analyzed. Posterior fossa conformity of 3D photons came at the expense of increasing amounts of normal tissue receiving low to moderate doses.

Child↗
PubMed2000

Expression of various multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells.

Multidrug resistance-associated protein (MRP) actively transports a broad range of anionic compounds out of the cell. To date, six different homologues of MRP (i.e. MRP1-MRP6) have been identified. The current study examines the expression of the various MRP homologues in both primary cultured bovine brain microvessel endothelial cells (BBMEC) and the capillary-enriched fraction from bovine brain homogenates. RT-PCR analysis demonstrated the presence of MRP1, MRP4, MRP5 and MRP6 in both BBMEC and the capillary-enriched fractions of brain homogenates. While low levels of MRP3 were detected in the BBMEC, it was not observed in the capillary-enriched fraction. In addition, RT-PCR and Western blot studies indicated an absence of MRP2 expression in both blood-brain barrier preparations. The presence of several different MRP homologues in the brain microvessel endothelial cells may be important in controlling the permeability of the blood-brain barrier to organic anions.

ATP-Binding Cassette Transporters↗
PubMed2000

Sample preparation for the analysis of flavors and off-flavors in foods.

Off-flavors in foods may originate from environmental pollutants, the growth of microorganisms, oxidation of lipids, or endogenous enzymatic decomposition in the foods. The chromatographic analysis of flavors and off-flavors in foods usually requires that the samples first be processed to remove as many interfering compounds as possible. For analysis of foods by gas chromatography (GC), sample preparation may include mincing, homogenation, centrifugation, distillation, simple solvent extraction, supercritical fluid extraction, pressurized-fluid extraction, microwave-assisted extraction, Soxhlet extraction, or methylation. For high-performance liquid chromatography of amines in fish, cheese, sausage and olive oil or aldehydes in fruit juice, sample preparation may include solvent extraction and derivatization. Headspace GC analysis of orange juice, fish, dehydrated potatoes, and milk requires almost no sample preparation. Purge-and-trap GC analysis of dairy products, seafoods, and garlic may require heating, microwave-mediated distillation, purging the sample with inert gases and trapping the analytes with Tenax or C18, thermal desorption, cryofocusing, or elution with ethyl acetate. Solid-phase microextraction GC analysis of spices, milk and fish can involve microwave-mediated distillation, and usually requires adsorption on poly(dimethyl)siloxane or electrodeposition on fibers followed by thermal desorption. For short-path thermal desorption GC analysis of spices, herbs, coffee, peanuts, candy, mushrooms, beverages, olive oil, honey, and milk, samples are placed in a glass-lined stainless steel thermal desorption tube, which is purged with helium and then heated gradually to desorb the volatiles for analysis. Few of the methods that are available for analysis of food flavors and off-flavors can be described simultaneously as cheap, easy and good.

Flavoring Agents↗