Translation Between Two Models; Application with Integrated Glucose Homeostasis Models.

PURPOSE: For some biological systems, there exist several models with somewhat different features and perspectives. We propose an evaluation method for NLME models by analyzing real and simulated data from the model of main interest using a structurally different, but similar, NLME model. We showcase this method using the Integrated Glucose Insulin (IGI) model and the Integrated Minimal Model (IMM). Additionally, we try to map parameters carrying similar information between the two models. METHODS: A bootstrap of real data and simulated datasets from both the IMM and IGI models were analyzed with the two models. Important parameters of the IMM were mapped to IGI parameters using a large IMM simulated dataset analyzed under the IGI model. RESULTS: Comparison of the parameters estimated from real data and data simulated with the IMM and analyzed with the IGI model demonstrated differences between real and IMM-simulated data. Comparison of the parameters estimated from real data and data simulated with the IGI model and analyzed with the IMM also demonstrated differences but to a lower extent. The strongest parameter correlations were found for: insulin-dependent glucose clearance (IGI) ~ insulin sensitivity (IMM); insulin-independent glucose clearance (IGI) ~ glucose effectiveness (IMM); and insulin effect parameter (IGI) ~ insulin action (IMM). CONCLUSIONS: We demonstrated a new approach to investigate models' ability to simulate real-life-like data, and the information captured in each model in comparison to real data, and the IMM clinically used parameters were successfully mapped to their corresponding IGI parameters.

The potential effects of silver and gold nanoparticles as molluscicides and cercaricides on Schistosoma mansoni.

Schistosomiasis seriously affects human health in tropical regions. Its prevention is more important than treatment, raising the need for effective control methods. Recently, the role of nanomaterials in medical science has been growing. The present study aimed to evaluate the potential effects of silver (Ag) and gold (Au) nanoparticles (NPs) on Biomphalaria alexandrina snails and Schistosoma mansoni cercariae in vitro and to assess their effects on the infectivity of cercariae in vivo. The in vitro study proved that Ag and Au NPs were effective in killing B. alexandrina snails, with 30 µg/ml Ag and 160 µg/ml Au causing 100% mortality. The LC50 of 9.68 µg/ml for Ag NPs and 133.7 µg/ml for Au NPs prevented snail infection with S. mansoni miracidia. Furthermore, Ag NPs at 50 µg/ml and Au NPs at 100 µg/ml increased the mortality of S. mansoni cercariae in a dose- and time-dependent manner, reaching 100% mortality after 1 h. The in vivo study found that Ag NPs prevented the occurrence of infection when cercariae were treated before the infection by either the tail immersion (TI) or subcutaneous (SC) route, as proven by parasitological parameters and by the absence of granuloma formation in hepatic tissue. Meanwhile, infection of mice by untreated cercariae followed by treatment with NPs 1 h post-infection (PI) caused a decrease in egg count/g intestine and egg count/g liver in the TI-infected group only. The oogram patterns and granuloma formation results were similar between infection control and the SC-infected group. On the other hand, Au NPs led to a decrease in total worm burden (TWB) in all tested groups, with a decrease in egg count/g intestine and egg count/g liver in TI-infected groups with either pre-treated or post-treated cercariae, in contrast to SC-infected groups. However, the oogram patterns and granuloma formation showed similar results to infection control. Ag and Au NPs have potential as molluscicides and cercaricides in vitro and can prevent or modulate the infectivity of cercariae in vivo.

Molecular xenomonitoring (MX) and transmission assessment survey (TAS) of lymphatic filariasis elimination in two villages, Menoufyia Governorate, Egypt.

Lymphatic filariasis (LF) is focally endemic in Egypt where the female mosquito, Culex pipiens, is responsible for its transmission. The aim of the study was to investigate the impact of implementation of the 13th round of MDA in two Egyptian villages in the Menoufyia Governorate area after failing the transmission assessment survey (TAS) in 2005 using two methods, and to decide whether it is safe to stop MDA in these, as well as in similar implementation units (IUs). To achieve this aim, both the immunochromatographic card test (ICT) and molecular xenomonitoring (MX) techniques were employed. A cross-sectional study was carried out in the villages in 2014 with two sections: Section (1): a school-based survey where all the primary school entrants (6-7) years of age were tested by ICT. Section (2): a mosquito-based survey where a total of 152 mosquito pools collected from Samalay and 167 from Kafr El-Tarainah were tested for the presence of the gDNA of Wuchereria bancrofti microfilaria by real-time PCR assays. The results revealed that all primary school children in both villages were 100% negative for antigenemia. Also, all mosquito pools were 100% negative for the microfilarial gDNA.

One-Year Prospective Study of Community Acquired Influenza and Parainfluenza Viral Infections in Hospitalized Egyptian Children with Malignancy: Single Center Experience.

BACKGROUND: Respiratory viruses are widespread in the community and easily transmitted to immunocompromised patients. AIMS: Assess the prevalence of community-acquired respiratory viral infections among children with cancer presenting with clinical picture suggestive of lower respiratory tract infections (LRTIs), and evaluate its risk factors and prognosis. METHODS: Over a year, 90 hospitalized children with malignancy and LRTIs recruited, subjected to clinical assessment, investigated through hematology panel, blood culture, chest x-ray, CT chest and PCR for influenza A and B, parainfluenza (PIV) types 1 and 3 viruses, and respiratory syncytial virus (RSV), and prospectively followed up for the clinical outcome. RESULTS: Viral pathogens were identified in 34 patients (37.7%), with a seasonal peak from April to May. The most frequently detected virus was influenza virus [type A (16 cases; 47%), type B (4 cases; 12%)] followed by parainfluenza virus [PIV1 (9 cases; 26%), PIV3 (3 cases; 15%)], and none had RSV. Bacteria were identified in 26 patients, fungi in four, mixed infections [bacterial/viral and bacterial/fungal] in 13, and 36 cases had unidentified etiology. The majority of patients with influenza and parainfluenza infections had hematological malignancy, presented with fever, and had mild self-limited respiratory illness. Five patients with mixed viral and bacterial infection had severe symptoms necessitating ICU admission. Six patients died from infection-related sequelae; two had mixed PIV and Staphylococcal infections. CONCLUSIONS: Community acquired influenza and parainfluenza infections are common in pediatrics patients with malignancy, either as isolated or mixed viral/bacterial infections. Clinical suspicion is essential as hematological and radiological manifestations are nonspecific. Rapid diagnosis and management are mandatory to improve patients' outcome.

Surveillance of lymphatic filariasis 5 years after stopping mass drug administration in Menoufiya Governorate, Egypt.

The World Health Organization recommends that before lymphatic filariasis elimination in an area can be confirmed, an additional survey should be performed at least 5 years after stopping mass drug administration. The current study aimed to determine the status of lymphatic filariasis 5 years after cessation ofthe mass drug administration in 3 sentinel Egyptian villages in Menoufiya Governorate. The rapid immunochromatographic card test (ICT) and a new commercial antibody detection kit (CELISA®) were used. All 1321 primary-school children aged 6-7 years old were ICT negative but 27 children were antibody positive. All households surveyed in one village with the highest antibody prevalence were ICT negative, indicating an absence of lymphatic filariasis. The CELISA antibody kit needs more standardization and development to be useful under field conditions. We conclude that lymphatic filariasis is no longer a public health problem in these villages and other villages with similar epidemiological conditions.

Impact of diet on human gut microbiome and disease risk.

The gut microbiome of humans comprises a diverse group of trillions of microorganisms including symbiotic organisms, opportunistic pathogens and commensal organisms. This microbiota plays a major role in digesting food; it also helps with absorbing and synthesizing some nutrients and releases their metabolites, which may deliver a variety of growth-promoting and growth-inhibiting factors that influence human health either directly or indirectly. The balance between microbial species, especially those responsible for the fermentation of different substrates within the microbial community, which are in the majority, depends on daily diet. Therefore, an unbalanced diet may lead to the progression and development of human diseases. These include metabolic and inflammatory disorders, cancer and depression, as well as infant health and longevity. We provide an overview of the effect of diet on the human microbiome and assess the related risk of disease development.

Optimal Designs for Model-Based Assessment of Insulin Sensitivity and Glucose Effectiveness.

The integrated minimal model allows assessment of clinical diagnosis indices, for example, insulin sensitivity (SI ) and glucose effectiveness (SG ), from data of the insulin-modified intravenous glucose tolerance test (IVGTT), which is laborious with an intense sampling schedule, up to 32 samples. The aim of this study was to propose a more informative, although less laborious, IVGTT design to be used for model-based assessment of SI and SG . The IVGTT design was optimized simultaneously for all design variables: glucose and insulin infusion doses, time of glucose dose and start of insulin infusion, insulin infusion duration, sampling times, and number of samples. Design efficiency was used to compare among different designs. The simultaneously optimized designs showed a profound higher efficiency than both standard rich (32 samples) and sparse (10 samples) designs. The optimized designs, after removing replicate sample times, were 1.9 and 7.1 times more efficient than the standard rich and sparse designs, respectively. After including practical aspects of the designs, for example, sufficient duration between samples and avoidance of prolonged hypoglycemia, we propose 2 practical designs with fewer sampling times and lower input of glucose and insulin than standard designs, constrained to prevent hypoglycemia. The optimized practical rich design is equally efficient in assessing SI and SG as the rich standard design, but with half the number of the samples, while the optimized practical sparse design has 1 less sample and requires 4.6 times fewer individuals for equal certainty when assessing SI and SG than the sparse standard design.

Pharmacokinetic modeling and simulation support for age- and weight-adjusted dosing of dabigatran etexilate in children with venous thromboembolism.

BACKGROUND: Dabigatran etexilate (DE), a direct oral thrombin inhibitor, has been evaluated in children with venous thromboembolism (VTE) using oral solution, pellets, or capsules. OBJECTIVES: This study evaluated DE pharmacokinetics (PK) in children with VTE and the appropriateness of a DE pediatric age- and weight-based dosing algorithm. PATIENTS/METHODS: A population PK model was fitted to data from four single-arm and one randomized, comparative pediatric VTE studies (358 children aged birth to <18 years; 2748 PK observations) and one healthy-adult study (32 males aged <40 years; 1523 PK observations) using nonlinear mixed-effects modeling. A stepwise, covariate, model-building procedure evaluated the influence of covariates (e.g., age, body weight, body surface area [BSA]-normalized renal function, and sex). The final model was used to evaluate the pediatric dosing algorithm, with simulations comparing pediatric trough exposure with reference exposure defined for the pediatric studies. RESULTS: The population PK of dabigatran was adequately described by a two-compartment model with first-order elimination and absorption. Age, weight, BSA-normalized renal function, and sex were statistically significant covariates (all P < .05). Apparent clearance increased with age (independently of body weight), diminished with decreasing BSA-normalized renal function, and was lower in females than males. All disposition parameters increased with body weight escalation (allometric scaling). Simulations confirmed that for all DE formulations, the final pediatric dosing algorithms achieved reference exposure without dose adjustment. CONCLUSIONS: Using a population PK model of DE for children with VTE, simulations showed that the final dosing algorithms were appropriate for all DE formulations; no dose titration was needed.

Variability Attribution for Automated Model Building.

We investigated the possible advantages of using linearization to evaluate models of residual unexplained variability (RUV) for automated model building in a similar fashion to the recently developed method "residual modeling." Residual modeling, although fast and easy to automate, cannot identify the impact of implementing the needed RUV model on the imprecision of the rest of model parameters. We used six RUV models to be tested with 12 real data examples. Each example was first linearized; then, we assessed the agreement in improvement of fit between the base model and its extended models for linearization and conventional analysis, in comparison to residual modeling performance. Afterward, we compared the estimates of parameters' variabilities and their uncertainties obtained by linearization to conventional analysis. Linearization accurately identified and quantified the nature and magnitude of RUV model misspecification similar to residual modeling. In addition, linearization identified the direction of change and quantified the magnitude of this change in variability parameters and their uncertainties. This method is implemented in the software package PsN for automated model building/evaluation with continuous data.

The integrated glucose insulin minimal model: An improved version.

This paper describes the improved integrated minimal model for healthy subjects and patients with type 2 diabetes and the work leading up to this model. The original integrated minimal model characterizes simultaneously glucose and insulin following intravenous glucose tolerance test (IVGTT) in healthy subjects and provides apart from estimates of indices for insulin sensitivity (Si) and glucose effectiveness (SG), also full simulation capabilities. However, this model was developed using IVGTT data of total glucose and consequently, the model cannot separate hepatic glucose production from glucose disposal. By fitting the original integrated minimal model to IVGTT data of labelled and total glucose, we show that all parameter estimates of the glucose sub-model were significantly different between the fits, in particular, SG, which was ~3 fold higher with total, compared to labelled glucose. In addition, the time profiles of hepatic glucose production, obtained from the model, were unphysiological in most subjects. To correct these flaws, we developed the improved integrated minimal model based on the non-integrated, two-compartment minimal model. The improved integrated minimal model showed physiologically plausible dynamic time profiles of hepatic glucose production and all parameter estimates were compatible with those reported in original publication of the non-integrated minimal model. The integrated minimal model offers the benefits of the original integrated minimal model with simulation capabilities, in presence of endogenous insulin, combined with the benefits of the non-integrated minimal model, which accurately estimates the clinical indices of insulin sensitivity and glucose effectiveness. In addition, the improved integrated minimal model describes, apart from healthy subjects, also patients with type 2 diabetes.

Model-Based Conditional Weighted Residuals Analysis for Structural Model Assessment.

Nonlinear mixed effects models are widely used to describe longitudinal data to improve the efficiency of drug development process or increase the understanding of the studied disease. In such settings, the appropriateness of the modeling assumptions is critical in order to draw correct conclusions and must be carefully assessed for any substantial violations. Here, we propose a new method for structure model assessment, based on assessment of bias in conditional weighted residuals (CWRES). We illustrate this method by assessing prediction bias in two integrated models for glucose homeostasis, the integrated glucose-insulin (IGI) model, and the integrated minimal model (IMM). One dataset was simulated from each model then analyzed with the two models. CWRES outputted from each model fitting were modeled to capture systematic trends in CWRES as well as the magnitude of structural model misspecifications in terms of difference in objective function values (ΔOFVBias). The estimates of CWRES bias were used to calculate the corresponding bias in conditional predictions by the inversion of first-order conditional estimation method's covariance equation. Time, glucose, and insulin concentration predictions were the investigated independent variables. The new method identified correctly the bias in glucose sub-model of the integrated minimal model (IMM), when this bias occurred, and calculated the absolute and proportional magnitude of the resulting bias. CWRES bias versus the independent variables agreed well with the true trends of misspecification. This method is fast easily automated diagnostic tool for model development/evaluation process, and it is already implemented as part of the Perl-speaks-NONMEM software.

Toward Highly Efficient Cancer Imaging and Therapy Using the Environment-Friendly Chitosan Nanoparticles and NIR Laser.

Chitosan-tripolyphosphate nanoparticles (C-TPP NPs) were synthesized to investigate their cytotoxicity against colon cancer cells (Caco2 cells) in the absence and the presence of a near-infrared (NIR) laser to evaluate their influence in cancer detection using the NIR laser and to evaluate the NIR laser on cancer treatment. The synthesized NPs were characterized by Fourier transform infrared (FT-IR) spectroscopy, dynamic light scattering (DLS), zeta potential (ZP), and transmission electronic microscope (TEM). The cytotoxicity was analyzed by the MTT test and the cell viability was assessed using the Trypan blue method. C-TPP NPs showed increased cytotoxicity and decreased cell viability against Caco2 cells. Upon laser exposure only, the cell viability decreased. The C-TPP NPs appeared to have a shining light on the cancerous cells which were photographed under the inverted microscope.

Model-Based Residual Post-Processing for Residual Model Identification.

The purpose of this study was to investigate if model-based post-processing of common diagnostics can be used as a diagnostic tool to quantitatively identify model misspecifications and rectifying actions. The main investigated diagnostic is conditional weighted residuals (CWRES). We have selected to showcase this principle with residual unexplained variability (RUV) models, where the new diagnostic tool is used to scan extended RUV models and assess in a fast and robust way whether, and what, extensions are expected to provide a superior description of data. The extended RUV models evaluated were autocorrelated errors, dynamic transform both sides, inter-individual variability on RUV, power error model, t-distributed errors, and time-varying error magnitude. The agreement in improvement in goodness-of-fit between implementing these extended RUV models on the original model and implementing these extended RUV models on CWRES was evaluated in real and simulated data examples. Real data exercise was applied to three other diagnostics: conditional weighted residuals with interaction (CWRESI), individual weighted residuals (IWRES), and normalized prediction distribution errors (NPDE). CWRES modeling typically predicted (i) the nature of model misspecifications, (ii) the magnitude of the expected improvement in fit in terms of difference in objective function value (ΔOFV), and (iii) the parameter estimates associated with the model extension. Alternative metrics (CWRESI, IWRES, and NPDE) also provided valuable information, but with a lower predictive performance of ΔOFV compared to CWRES. This method is a fast and easily automated diagnostic tool for RUV model development/evaluation process; it is already implemented in the software package PsN.

Study Design Selection in Early Clinical Anti-Hyperglycemic Drug Development: A Simulation Study of Glucose Tolerance Tests.

In antidiabetic drug development, phase I studies usually involve short-term glucose provocations. Multiple designs are available for these provocations (e.g., meal tolerance tests (MTTs) and graded glucose infusions (GGIs)). With a highly nonlinear, complex system as the glucose homeostasis, the various provocations will contribute with different information offering a rich choice. Here, we investigate the most appropriate study design in phase I for several hypothetical mechanisms of action of a study drug. Five drug effects in diabetes therapeutic areas were investigated using six study designs. Power to detect drug effect was assessed using the likelihood ratio test, whereas precision and accuracy of the quantification of drug effect was assessed using stochastic simulation and estimations. An overall summary was developed to aid designing the studies of antihyperglycemic drug development using model-based analysis. This guidance is to be used when the integrated glucose insulin model is used, involving the investigated drug mechanisms of action.

Model based population PK-PD analysis of furosemide for BP lowering effect: A comparative study in primary and secondary hypertension.

Though numerous reports have demonstrated multiple mechanisms by which furosemide can exert its anti-hypertensive response. However, lack of studies describing PK-PD relationship for furosemide featuring its anti-hypertensive property has limited its usage as a blood pressure (BP) lowering agent. Serum concentrations and mean arterial BP were monitored following 40 and 80mgkg-1 multiple oral dose of furosemide in spontaneously hypertensive rats (SHR) and DOCA-salt induced hypertensive (DOCA-salt) rats. A simultaneous population PK-PD relationship using Emax model with effect compartment was developed to compare the anti-hypertensive efficacy of furosemide in these rat models. A two-compartment PK model with Weibull-type absorption and first-order elimination best described the serum concentration-time profile of furosemide. In the present study, post dose serum concentrations of furosemide were found to be lower than the EC50. The EC50 predicted in DOCA-salt rats was found to be lower (4.5-fold), whereas the tolerance development was higher than that in SHR model. The PK-PD parameter estimates, particularly lower values of EC50, Ke and Q in DOCA-salt rats as compared to SHR, pinpointed the higher BP lowering efficacy of furosemide in volume overload induced hypertensive conditions. Insignificantly altered serum creatinine and electrolyte levels indicated a favorable side effect profile of furosemide. In conclusion, the final PK-PD model described the data well and provides detailed insights into the use of furosemide as an anti-hypertensive agent.

Phenobarbital solubility in propylene glycol-glycerol-water systems.

Phenobarbital solubility in various binary and ternary propylene glycol-glycerol-water solvent systems was determined. Phenobarbital concentrations several times those of the ethanol-containing USP and BPC elixirs were obtained. From log solubility-solvent composition plots, a general equation was developed for phenobarbital solubility prediction in propylene glycol-water, glycerol-water, and propylene glycol-glycerol-water solvent systems. Solubility predictions using another equation, based on linear log solubility-dielectric constant relationships, were limited by the need to use different constants for different solvent blends. Heats of solution for phenobarbital determined in selected solvent blends as well as in USP and BPC elixirs varied within a very narrow range, suggesting similar solute-solvent interactions.

Succinylsulfathiazole crystal forms. II: Effect of additives on kinetics of interconversion.

The effect of various additives on the rate of transformation of the metastable anhydrous succinylsulfathiazole Form I to the water-stable dihydrate Form II in aqueous suspensions was studied. Some structurally related compounds, viscosity-imparting agents, surfactants, and coloring agents were used as possible transformation retardants. The effect of including seeds of Form II in the presence and absence of additives is also discussed. Some additives, e.g., methylcellulose and phthalysulfathiazole, showed significant transformation-retarding effects. Other additives, e.g., sulfanilamide and glycerin, increased the rate of transformation. Coloring agents had only slight effects. Utilization of the results in the formulation of physically stable aqueous suspensions of succinylsulfathiazole is discussed.

Succinylsulfathiazole crystal forms. III: Crystal growth studies.

Crystal growth accompanying the transformation of succinylsulfathiazole crystal forms in aqueous suspensions was studied using a projecting microscope. The effects of increase of temperature, agitation, inclusion of seeds of Form II (the water-stable dihydrate), sulfathiazole, methylcellulose, and polysorbate 80 on the particle-size distribution of anhydrous succinylsulfathiazole Form I were examined. Rates of crystal growth, calculated as increase of diameter per unit time, were given under different experimental conditions. Increase of temperature, agitation, and seeding with nuclei of Form II had significant growth-accelerating effects. Sulfathiazole and polysorbate 80 had growth-retarding effects. Methylcellulose inhibited the crystal growth of Form I for over a year. Aqueous suspensions of Form II did not show any change in particle-size distribution. The crystal growth was shown to be a direct consequence of the transformation of the crystal form. Physical conditions and additives which had accelerating or retarding effects on the rate of succinylsulfathiazole in aqueous suspensions.

Accumulation of lead and cadmium in the marine prosobranch Nerita saxtilis, chemical analysis, light and electron microscopy.

The potential value of the marine prosobranch Nerita saxtilis as an efficient biological monitor to heavy metal pollution in the Red Sea was investigated. Storage ability of lead and cadmium was compared in shell, headfoot and digestive gland of the marine snail N. saxtilis collected from Al-Hamrauin area at El-kuseir (lead, 300.35 +/- 28.53 microg/l, 1,716 +/- 16.14. cadmium 20.01 +/- 1.8 microg/l, 161.72 +/- 21.4 mean +/- S.D. for water and sediment, respectively) relative to that of inhabiting marine water and sediment employing atomic absorption spectrometry to determine the organ with highest capability of heavy metal accumulation. The influence of metal storage on light microscopic structure of that organ was investigated. Also, the ultrastructure localization of storage sites in the same organ was determined employing transmission electron microscopy. The digestive gland was shown to accumulate both metals at conccntrations that are several orders of magnitude higher than those in the surrounding marine water. The bioaccumulation capability of lead and cadmium was ranked in the following order; digestive gland > headfoot > shell for lead and digestive gland > shell > headfoot for cadmium. In spite of its evident highest metal storage capability, no histopathological changes were observed in the digestive gland of that marine prosobranch. Enlarged electron dense vesicles and many granules were observed in ultrathin sections in digestive cells of these snails and are suggested to be the sites of storage of detoxified metals. The results of that finding indicate the possibility of using the marine prosobranch N. saxtilis as biomonitor for heavy metal contaminants in the Red Sea.

Percentages of the deuterium retained after para-hydroxylation of (R)(+)4-2H-phenytoin and (S)(-) 4-2H-phenytoin in rat.

(R)(+) and (S)(-) 4-2H-phenytoin have been used as substrates for the determination of the percentage of deuterium retention (NIH shift) after para-hydroxylation of the substrates in rat. By using GC-MS analyses, the percentages of deuterium retention were found to be 69% and 70% for the (R) and (S) phenyl rings, respectively. The results add additional evidence for the involvement of arene oxide in the oxidation of the pro (R) and pro (S) phenyls of phenytoin. The oxidation process of each ring could be mediated by independent enzyme systems, a rapid oxidative enzyme for the pro (S) phenyl and a slow oxidative enzyme for the pro (R) phenyl.