scholarly journals ENZYME VARIATION, METABOLIC FLUX AND FITNESS: ALCOHOL DEHYDROGENASE IN DROSOPHILA MELANOGASTER

Genetics ◽  
1983 ◽  
Vol 105 (3) ◽  
pp. 633-650
Author(s):  
Richard J Middleton ◽  
Henrik Kacser
Keyword(s):  
Metabolic Flux ◽  
Mean Value ◽  
In Vivo Studies ◽  
Standard Errors ◽  
In Vitro Activity ◽  
Enzyme Variation ◽  
Flux Level ◽  
The Mean

ABSTRACT Although there are many in vitro studies of enzyme activity of genetic variants at the Adh locus in D. melanogaster, little is known about the corresponding metabolic activity in living flies. We report here such measurements of the metabolic flux in the conversion of ethanol to the two products, CO2 and lipids, for six different active genotypes, containing the predominant naturally recurring alleles and covering a threefold range of in vitro activity. In adult flies we have found nonsignificant differences between genotypes in metabolic flux when estimates for individual genotypes had standard errors of approximately 10% of the mean value. In vitro activities are, therefore, poor predictors of the physiological consequences of enzyme variation since such determinations ignore the interactions inherent in multienzyme systems. We have no evidence that heterozygote show overdominance either at the enzyme or the flux level. Since fitness differences between genotypes must be generated by physiological differences, investigations of polymorphisms should be based on in vivo studies.

scholarly journals Formulation and in vitro evaluation of self-nanoemulsifying liquisolid tablets of furosemide

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lena Dalal ◽  
Abdul Wahab Allaf ◽  
Hind El-Zein
Keyword(s):  
Theoretical Model ◽  
Castor Oil ◽  
In Vivo Studies ◽  
Coating Materials ◽  
Peg 400 ◽  
The Mean ◽  
Usp Apparatus ◽  
Solid System

AbstractSelf-nanoemulsifying drug delivery systems (SNEDDS) were used to enhance the dissolution rate of furosemide as a model for class IV drugs and the system was solidified into liquisolid tablets. SNEDDS of furosemide contained 10% Castor oil, 60% Cremophor EL, and 30% PEG 400. The mean droplets size was 17.9 ± 4.5 nm. The theoretical model was used to calculate the amounts of the carrier (Avicel PH101) and coating materials (Aerosil 200) to prepare liquisolid powder. Carrier/coating materials ratio of 5/1 was used and Ludipress was added to the solid system, thus tablets with hardness of 45 ± 2 N were obtained. Liquisolid tablets showed 2-folds increase in drug release as compared to the generic tablets after 60 min in HCl 0.1 N using USP apparatus-II. Furosemide loaded SNEDDS tablets have great prospects for further in vivo studies, and the theoretical model is useful for calculating the adequate amounts of adsorbents required to solidify these systems.

scholarly journals In Vivo Efficacy of Anidulafungin and Caspofungin against Candida glabrata and Association with In Vitro Potency in the Presence of Sera

2007 ◽  
Vol 51 (5) ◽  
pp. 1616-1620 ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
Rosie Bocanegra ◽  
Destiny Molina ◽  
Marcos Olivo ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Animal Studies ◽  
Kidney Tissue ◽  
Vitro Activity ◽  
In Vivo Studies ◽  
In Vitro Activity ◽  
In Vivo Efficacy ◽  
Fungal Burden

ABSTRACT In vitro studies have demonstrated that anidulafungin has greater potency than caspofungin against Candida glabrata. However, data from in vivo studies demonstrating that it has superior efficacy are lacking. The objective of this study was to compare the activities of anidulafungin and caspofungin against C. glabrata in a murine model of disseminated candidiasis. Two clinical C. glabrata isolates were used, including one with reduced caspofungin susceptibility. MICs were determined by broth microdilution in the presence and absence of sera. For the animal studies, mice were immunosuppressed with 5-fluorouracil one day prior to intravenous inoculation. Treatment with anidulafungin and caspofungin (0, 0.5, 1, 5, and 10 mg/kg of body weight per day) was begun 24 h later and was continued through day 7 postinoculation. The CFU were enumerated from kidney tissue. According to the standard microdilution methodology, anidulafungin had superior in vitro activity. However, this enhanced potency was attenuated by the addition of mouse and human sera. Caspofungin reduced the kidney fungal burden at lower doses compared to that achieved with anidulafungin in mice infected with the isolate with the lower MIC. Against the strain with the elevated caspofungin MIC, both anidulafungin and caspofungin were effective in reducing the kidney fungal burden at the higher doses studied. Despite the greater in vitro activity of anidulafungin in the absence of sera, both echinocandins were similarly effective in reducing the fungal burden in kidney tissue. The superior in vitro activity of anidulafungin did not confer enhanced in vivo efficacy against C. glabrata.

scholarly journals Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as Novel Treatment Options for Schistosomiasis

2020 ◽  
Author(s):  
Valentin Buchter ◽  
Yih Ching Ong ◽  
François Mouvet ◽  
Abdallah Ladaycia ◽  
Elise Lepeltier ◽  
...  
Keyword(s):  
Treatment Options ◽  
Vitro Activity ◽  
In Vivo Studies ◽  
In Vitro Activity ◽  
Liver Model ◽  
Novel Treatment ◽  
Active Concentration ◽  
Dynamics Simulations

<div>Schistosomiasis is a disease of poverty affecting millions of people. Praziquantel (PZQ), with its </div><div>strengths and weaknesses, is the only treatment available. We previously reported 3 lead </div><div>compounds derived from oxamniquine (OXA), an old antischistosomal drug: ferrocene‐containing </div><div>(Fc‐CH2‐OXA), ruthenocene‐containing (Rc‐CH2‐OXA) and benzene‐containing (Ph‐CH2‐OXA). </div><div>These derivatives showed excellent in vitro activity against both Schistosoma mansoni and S. </div><div>haematobium larvae and adult worms, and in vivo against S. mansoni. Encouraged by these </div><div>promising results, we followed a guided drug discovery process and report in this investigation on </div><div>metabolic stability studies, in vivo studies, computational simulations, and formulation studies. </div><div>Molecular dynamics simulations supported the in vitro results on the target protein. Though all </div><div>three compounds were poorly stable within an acidic environment, they were only slightly cleared </div><div>in the in vitro liver model. This is likely the reason as to why the promising in vitro activity did not </div><div>translate to in vivo activity. This limitation could not be saved by the formulation of lipid </div><div>nanocapsules as an intent to improve the in vivo activity. Further studies should focus on increasing </div><div>the compound’s bioavailability, in order to reach an active concentration in the parasite’s </div><div>microenvironment. </div>

In Vitro and in Vivo Measurement of Total Antiplasmin Activity

1977 ◽  
Vol 37 (02) ◽  
pp. 216-221 ◽  
Author(s):  
Osamu Matsuo ◽  
Hisashi Mihara
Keyword(s):  
Plasma Volume ◽  
Fibrinolytic Activity ◽  
Mean Value ◽  
Rabbit Plasma ◽  
In Vivo Measurement ◽  
The Mean ◽  
Infusion Speed

SummaryTotal antiplasmin was measured in vitro and in vivo. In the former case, rabbit plasma was mixed with various concentrations of Urokinase (UK) and the least concentration for appearance of fibrinolytic activity was estimated. This concentration was multiplied by the plasma volume of the rabbit to give the in vitro total antiplasmin. The mean value for 14 rabbits was 4,068.6 units.In order to estimate the total antiplasmin in vivo, UK solution was infused into rabbits. The infusion speed was multiplied by the time of the first appearance of fibrinolytic activity to give the total antiplasmin, although when the infusion speed was low, fibrinolytic activity did not appear during infusion. The mean in vivo total antiplasmin calculated for 6 cases where the infusion speed was high and fibrinolytic activity was observed, was 28,699.8 units, i.e. about 7 (range, 3-11) times the in vitro value.

Assembly of three major subclasses of mouse immunoglobulin G: a theoretical model for covalent assembly in vivo

1976 ◽  
Vol 54 (8) ◽  
pp. 688-698 ◽  
Author(s):  
J. R. Percy ◽  
M. E. Percy ◽  
R. Baumal
Keyword(s):  
Cell Lines ◽  
Immunoglobulin G ◽  
Mean Value ◽  
Individual Values ◽  
In Vitro Assembly ◽  
The Mean ◽  
The Individual ◽  
Mouse Myeloma

A mathematical model, based on second-order reaction kinetics, has been used to describe the covalent assembly of immunoglobulin G (IgG) in vitro from its heavy (H) and light (L) chains (Percy, M. E., Baumal, R., Dorrington, K. J. &Percy, J. (1976) Can. J. Biochem. 54, 675–687). In the present paper, the same model has now been applied to the steady-state assembly of IgG in vivo. This mathematical approach permits a quantitative comparison of the pathways of covalent assembly used by given immunoglobulins in vivo and in vitro. The assumptions in the model are: the species L, H, HL, HH, HHL and LHHL belong to a common pool; incompleted IgG intermediates may freely assemble to form HL, HH, HHL and LHHL; the reaction rate for covalent linkage between any two reacting species is proportional to the products of the number densities of the reactants and to a parameter P which takes the value PHH if the reaction joins two H chains, and PHL if it joins an H and L chain. In vivo values of PHH/PHL were determined for the 18 mouse myeloma tumours and cell lines studied by Baumal et al. (Baumal, R., Potter, M. &Scharff, M. (1971) J. Exp. Med. 134, 1316–1334). From these analyses, we have arrived at the following conclusions: (1) the three major IgG subclasses have distinctive values of PHH/PHL (mean value 53 for IgG1, 12 for IgG2a and 2.8 for IgG2b); (2) for IgGs of the same subclass, the values of PHH/PHL are similar; (3) the mean in vivo values of PHH/PHL are very close to those determined from in vitro assembly experiments. Finally, the individual values of PHH/PHL have been used to simulate pulse-chase experiments in the various tumours and cell lines. Considering the sources and magnitude of experimental error, the theoretical pathways of assembly agree with those determined qualitatively from the pulse-chase experiments.

Blood Gases of the Tench (Tinca tinca) in Well Aerated and Oxygen-Deficient Waters

1974 ◽  
Vol 60 (1) ◽  
pp. 71-83 ◽  
Author(s):  
F. B. EDDY
Keyword(s):  
Venous Blood ◽  
Oxygen Affinity ◽  
Blood Gases ◽  
Mean Value ◽  
Hypoxic Conditions ◽  
Arterial Blood ◽  
The Mean ◽  
Tench Tinca Tinca

1. The respiration of tench at 13°C was investigated, particular attention being given to the role of the blood in uptake and transport of oxygen. 2. In well aerated water the mean value for arterial blood was 36 mmHg, for PCOCO2 3.3 mmHg and for pH 8.16; the respective venous values were 7 mmHg, 5 mmHg and 8.08. Arterial blood averaged about 75% and venous blood about 40° oxygen saturation. The mean value for oxygen uptake was 0.5 ml/min/kg and for ventilation volume 132/ml/mm/kg. 3. The oxygen tension and the percentage saturation of the blood determined in vivo are discussed in terms of the oxygen dissociation curve determined in vitro. 4. When the environmental POO2 was decreased, tench responded by increasing breathing rate and ventilation volume. Arterial POO2 and PCOCO2 decreased but arterial pH tended to remain steady. There was also a significant increase in blood lactate. 5. That tenth can withstand severe hypoxic conditions is attributed to blood of high oxygen affinity and the ability to maintain a favourable acid-base status in the blood for oxygen transport. 6. Respiration in tench is compared with that in other fish species.

scholarly journals In vitro activity of six antiviral drugs against equid alphaherpesvirus type 1 indicates ganciclovir as promising drug for in vivo studies

2018 ◽  
Vol 48 (12) ◽  
Author(s):  
Amanda Lovato de Oliveira ◽  
Juliana Felipetto Cargnelutti ◽  
Ana Paula Gnocato Mortari ◽  
Eduardo Furtado Flores ◽  
Rudi Weiblen
Keyword(s):  
Specific Treatment ◽  
Vitro Activity ◽  
In Vivo Studies ◽  
In Vitro Activity ◽  
In Vivo Experiments ◽  
Drug Concentrations ◽  
Viral Plaque

ABSTRACT: Equid alphaherpesvirus type 1 (EHV-1) is distributed worldwide and is a major agent of abortion, respiratory and neurological disease in horses. No specific treatment is available for EHV-1 infection, yet the potential of antiviral therapy has been explored. In this study we investigated the in vitro activity of Acyclovir, Ganciclovir, Foscarnet, Famciclovir, Vidarabina and Cidofovir against EHV-1. For this, the MTT test was performed, in which all the tested drugs showed no toxicity up to 200μg/mL. Subsequently, different drug concentrations were submitted to viral plaque reduction assays in cell culture. The selectivity index (SI) of the compounds was determined using the cytotoxic concentration for 50% of cells (CC50), obtained by MTT, and effective drug concentration to inhibit by 50% the number of viral plaques (EC50). Ganciclovir (SI: 490; EC50: 1.9 μg/mL) was the most efficient and safest drug against EHV-1, followed by Cidofovir (SI: 150, EC50: 5.7μg/mL), Acyclovir (SI: 37.4, EC50: 22.2μg/mL), Famciclovir (SI: 25.1, EC50: 24.5μg/mL), Vidarabine (SI: 12.2, EC50: 40.9μg/mL) and Foscarnet (SI: 6.9, EC50: 49.5 μg/mL), respectively. These results indicated that Ganciclovir (followed by Cidofovir), is a promising candidate for use in in vivo experiments.

scholarly journals Evaluation of liquid sorption and color stability of dental composites after exposure to common lactation teas

2021 ◽  
Vol 11 (Suppl. 1) ◽  
pp. 228-233
Author(s):  
Zuhal Yıldırım Bilmez ◽  
Oya Şeker ◽  
Hazal Deniz Köse ◽  
Başak Gözüyeşil Aslan
Keyword(s):  
Composite Materials ◽  
Artificial Saliva ◽  
Color Stability ◽  
Mean Value ◽  
In Vivo Studies ◽  
Dental Composites ◽  
Primary Tooth ◽  
Significance Level

Aim: To assess the effects of common lactation teas on liquid sorption and color stability of three different dental composites. Methodology: A total of 60 samples (n = 5) were examined from three composite materials: Omnichroma (Tokuyama Dental Co., Tokyo, Japan), Estelite Posterior, (Tokuyama Dental Co., Tokyo, Japan), and Mosaic Universal (Ultradent production Inc., South Jordan, UT, USA). Samples measuring 2x6 mm were taken and immersed in three different teas—Humana (Humana, Bremen, Germany), Hipp, (Hipp, Pfaffenhofen, Germany), and Lactamil (Nutricia, Friedrichsdorf, Germany) —as well as artificial saliva. The measurements were recorded at baseline and on the 7th day. A sensitive analytical balance was used to measure liquid sorption, and a VITA Easy Shade device was used for color measurements. Absorption and Delta E values ​​were calculated. The data were analyzed using MANOVA at a significance level of (p<0.05). Results: Composite materials, solutions, and their interactions had a statistically significant effect on the sorption and Delta E values (p<0.001). The relative liquid absorption values among the composites were recorded as follows: Tokuyama>Mosaic>Omnichroma. Humana had the highest and Hipp had the lowest mean value among the solutions (p<0.001). For Delta E, Mosaic had the highest mean value among the composites, and Lactamil had the highest mean value among the solutions (p<0.001). Conclusion: Lactation teas cause discoloration in dental composites. In vitro and in vivo studies on color changes in dental composites are needed due to the sorption of these fluids.   How to cite this article: Özüdoğru S, Tosun G. Survival and clinical evaluation of various space maintainers used for early primary tooth loss. Int Dent Res 2021;11(Suppl.1):222-7. https://doi.org/10.5577/intdentres.2021.vol11.suppl1.32     Linguistic Revision: The English in this manuscript has been checked by at least two professional editors, both native speakers of English.

Effect of ketoconazole administration on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 13016-13016
Author(s):  
G. S. Chatta ◽  
M. E. Rader ◽  
C. P. Belani ◽  
S. Ramalingam ◽  
E. X. Chen ◽  
...  
Keyword(s):  
Cell Lymphoma ◽  
Proteasome Inhibition ◽  
In Vivo Studies ◽  
Advanced Malignancies ◽  
Significant Difference ◽  
Mantle Cell ◽  
The Mean ◽  
To Receive

13016 Background: Bortezomib (btz; VELCADE) is a first-in-class small molecule proteasome inhibitor used to treat patients with multiple myeloma and mantle cell lymphoma. In vitro and in vivo studies indicate that btz is primarily metabolized by CYP3A4 and CYP2C19. We conducted a study to evaluate the effect of inhibition of CYP3A4 with ketoconazole (keto) on the PK of btz in humans. Methods: The study enrolled patients with advanced malignancies for whom standard therapy was not available. Patients received btz 1.0mg/m2 (IV) on days 1, 4, 8, and 11 of a 21-day cycle, and were randomized to receive keto 400mg (PO) on days 6, 7, 8, and 9 of either the first or second cycle of treatment. Blood samples for plasma btz determination were collected over 72 hours following the Day 8 dose in Cycles 1 and 2. PK parameters were computed non-compartmentally. PD parameters were derived from an Emax model of percentage proteasome inhibition in whole blood. Results: Of the 21 patients enrolled, 13 had sufficient PK sampling in Cycles 1 and 2 to assess the effect of keto on the PK of btz. No statistically significant difference in AUC0–72h for btz ± keto was observed (p=0.2248). The mean AUC0–72h ratio was 1.22 (90% CI, 0.92–1.61). The exposure-PD relationships for btz ± keto were similar (Table). Adverse events were similar in the presence and absence of keto. Conclusions: Although the AUC0–72h difference was not statistically significant, the 90% CI for the AUC0–72h ratio extends beyond the FDA- specified range of 0.80–1.25 for DDI studies, precluding a declaration of no effect. The presence of a strong CYP3A4 inhibitor increased mean btz exposure by only 22% and had no apparent effect on the exposure-PD relationship. [Table: see text] No significant financial relationships to disclose.

In-Silico Model for Predicting CYP2D6-Mediated Drug-Drug Interactions

2020 ◽  
Vol 15 ◽  
Author(s):  
Roberto Lozano ◽  
Alberto Frutos ◽  
Alejandro Martinez
Keyword(s):  
Drug Interaction ◽  
Therapeutic Range ◽  
Area Under Curve ◽  
Inhibitory Concentration ◽  
Mean Value ◽  
Inhibition Constant ◽  
Constant Ratio ◽  
The Mean

Background: Successful integration of in vitro into in vivo data on drug-drug interaction (DDI) is dependent on the inhibitory concentration used. Obtaining plasma concentration of a drug is only readily available for a small number of drugs in clinical practice, and so we propose the use of a therapeutic range as a substitute for inhibitory concentration. Objective: Because of this, we aimed to construct a linear-regression model based on the area-under-curve of the victim drugs and the therapeutic range, for a set of known inhibitors of the CYP2D6 of interest. Methods: Correlation analysis of linear log-log regression of two main variables: the area-under-curve ratio (AUCr) of the victim drugs and of the therapeutic range-to-inhibition constant ratio, with data obtained from literature. Results: Data were fitted to a linear log-log regression, between the average of the AUCr values and the mean value of the therapeutic range-to-inhibition constant ratio (TRm-to-Ki), of the inhibitory drugs. Conclusions: According to our results, knowledge of the inhibition constant and therapeutic range (or its plasma levels if disponible) of the inhibitor would be sufficient to determine the intensity and clinical relevance of a CYP2D6-mediated DDI.

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