10 research outputs found
Cost considerations in the treatment of colorectal cancer
No full textColorectal cancer is among the most common malignancies in developed countries. Screening can reduce mortality significantly, although the most appropriate method is still under debate. Observational studies have revealed that lifestyle measures may also be beneficial for prevention of colorectal cancer. Surgery is still the most effective treatment modality for colorectal cancer. The survival benefits of chemotherapy are only modest. For nearly 5 decades, 5-fluorouracil (5-FU) has been the main cytotoxic agent for treatment of colorectal cancer. In the last decade, the new cytotoxic agents raltitrexed, irinotecan and oxaliplatin have been introduced, next to the oral 5-FU analogues capecitabine and tegafur in combination with uracil (UFT). Moreover, the immunotherapeutics bevacizumab and cetuximab have become approved for treatment of metastatic colorectal cancer. The economic implications of colorectal cancer treatment are substantial. The costs of treatment are mainly attributable to the early and terminal stage of the disease (i.e. surgery, hospitalisation, chemo- and immunotherapy and supportive care). The introduction of new chemo- and immunotherapeutics has caused a continuing increase of treatment expenditures. Therefore, comparative costs and cost effectiveness are important for assessing the value of new treatment regimens. The available study results suggest that addition of irinotecan or oxaliplatin to 5-FU/folinic acid dosage regimens is cost effective. Also, capecitabine is calculated to be cost effective when compared with 5-FU/folinic acid. For UFT, no comparative studies of cost effectiveness were found. Since raltitrexed and 5-FU/ folinic acid have shown equal efficacy in terms of survival, cost-effectiveness analysis is considered not to be applicable and cost-minimisation analysis may be sufficient. At present, pharmacoeconomic analyses of combination treatment with the immunotherapeutics bevacizumab or cetuximab are not available, except for recent cost-effectiveness considerations by the UK National Institute for Health and Clinical Excellence with negative recommendations for both agents in the treatment of metastatic colorectal cancer. Given the high treatment costs, substantial toxicity and relatively limited efficacy of the fast changing chemo- and immunotherapeutic combinations for colorectal cancer, examination of cost-effectiveness studies should be conducted on a routine basis along with determination of clinical benefits
Surfactant-free Preparation of Highly Stable Zwitterionic Poly(amido amine) Nanogels with Minimal Cytotoxicity
No full textNarrowly dispersed zwitterionic poly(amido amine) (PAA) nanogels with a diameter of approximately 100 nm were prepared by a high-yielding and surfactant-free, inverse nanoprecipitation of PAA polymers. The resulting, negatively charged, nanogels (PAA-NG1) were functionalized with N,N-dimethylethylenediamine via EDC/NHS coupling chemistry. This resulted in nanogels with a positive surface charge (PAA-NG2). Both types of nanogels were fluorescently labelled via isothiocyanate coupling. PAA-NG1 displays high colloidal stability both in PBS and Fetal Bovine Serum solution. Moreover, both nanogels exhibit a distinct zwitterionic swelling profile in response to pH changes. Cellular uptake of FITC-labelled nanogels with RAW 264.7, PC-3 and COS-7 cells was evaluated by fluorescence microscopy. These studies showed that nanogel surface charge greatly influences nanogel–cell interactions. The PAA polymer and PAA-NG1 showed minimal cell toxicity as was evaluated by MTT assays. The findings reported here demonstrate that PAA nanogels possess interesting properties for future studies in both drug delivery and imaging
Evidence- and consensus-based guidelines for drug-drug interactions with anticancer drugs; a practical and universal tool for management
No full textDrug-drug interactions (DDIs) with anticancer drugs are common and can significantly affect efficacy and toxicity of treatment. Therefore, a Dutch Multidisciplinary Expert group is assessing the clinical signifi-cance of DDIs in oncology and provides recommendations for the management of these DDIs. We present an overview of methodology and outcome of an evidence-and consensus-based assessment of DDIs be-tween anticancer drugs and non-anticancer drugs.A literature search was performed through PubMed and EMA and FDA assessment reports, to iden-tify potential DDI's involving anticancer drugs. For each potential DDI a concept report for risk analysis and practical advice for management was created. Subsequently, this risk analysis and the corresponding advice were assessed and weighed.A total of 290 potential DDIs have been identified in the literature thus far. Of these 290 potential DDIs, the Expert Group has identified 94 (32%) DDIs as clinically relevant, with a need for an automated alert and a suggested intervention. Furthermore, 110 DDIs have been identified as clinically not relevant. For 86 potential DDIs evidence supporting a relevant DDI was insufficient and in these cases neither an alert nor advice regarding a suggested intervention were formulated.A transparent risk analysis is presented for identification of clinically relevant DDIs with anticancer drugs. Integration of DDI guidelines into the national electronic prescribing system is essential to achieve optimal efficacy and minimal toxicity in patients receiving anticancer therapy. A clear overview of clin-ically relevant DDIs with anticancer therapy provides clinicians with a structured, evidence-based and consensus-built tool for anticancer therapy surveillance. (c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Personalised Therapeutic
Enhancing Separation Efficiency in European Syngas Industry by Using Zeolites
No full textSyngas is traditionally used in industry for production of fuels in the kerosene, gasoline and diesel range via Fischer-Tropsch, for the manufacture of bulk chemicals like ammonia, methanol and dimethyl ether and for synthesis of a whole array of fine chemicals. The carbon monoxide/hydrogen ratio of the syngas is an important design variable to maximize production of these compounds. Therefore, the search of effective processes that enable said ratio adjustment as well as individual compound purification is an essential and ongoing effort for industry. In this work, we propose a development of a zeolite-based separation process to obtain carbon dioxide-neutral fuels and chemicals. The process designed is based on gas uptake and release, combining separation efficiency with low separation costs. Calculation of separation behavior has been done for mixtures generated by plasmolysis of CO2. Carbon dioxide dissociation into CO and O2 and as a result a mixture of carbon monoxide, oxygen and a residual carbon dioxide is obtained. Therefore, the purification of CO becomes necessary. Here we provide a purification process design based in multicomponent adsorption and separation in commercial available zeolites. The process identifies NaX and NaY as the most suitable zeolites for separation in a wide range of operating conditions.</p
Perturbation of microbiota in one-day old broiler chickens with antibiotic for 24 hours negatively affects intestinal immune development
No full textBackground: Gut microbial colonization and development of immune competence are intertwined and are influenced by early-life nutritional, environmental, and management factors. Perturbation of the gut microbiome at young age affects the crosstalk between intestinal bacteria and host cells of the intestinal mucosa.Results: We investigated the effect of a perturbation of the normal early life microbial colonization of the jejunum in 1-day old chickens. Perturbation was induced by administering 0.8 mg amoxicillin per bird per day) via the drinking water for a period of 24 h. Effects of the perturbation were measured by 16S rRNA profiling of the microbiome and whole genome gene expression analysis. In parallel to what has been observed for other animal species, we hypothesized that such an intervention may have negative impact on immune development.Trends were observed in changes of the composition and diversity of the microbiome when comparing antibiotic treated birds with their controls. in the jejunum, the expression of numerous genes changed, which potentially leads to changes in biological activities of the small intestinal mucosa. Validation of the predicted functional changes was performed by staining immune cells in the small intestinal mucosa and a reduction in the number of macrophage-like (KUL01+) cells was observed due to a direct or indirect effect of the antibiotic treatment. We provide evidence that a short, early life antibiotic treatment affects both the intestinal microbiota (temporarily) and mucosal gene expression over a period of 2 weeks.Conclusion: These results underscore the importance of early life microbial colonization of the gut in relation to immune development and the necessity to explore the capabilities of a variety of early life dietary and/or environmental factors to modulate the programming for immune competence in broilers.<br/
Assessment of contaminants of emerging concern in European apex predators and their prey by LC-QToF MS wide-scope target analysis
No full textApex predators are good indicators of environmental pollution since they are relatively long-lived and their high trophic position and spatiotemporal exposure to chemicals provides insights into the persistent, bioaccumulative and toxic (PBT) properties of chemicals. Although monitoring data from apex predators can considerably support chemicals’ management, there is a lack of pan-European studies, and longer-term monitoring of chemicals in organisms from higher trophic levels. The present study investigated the occurrence of contaminants of emerging concern (CECs) in 67 freshwater, marine and terrestrial apex predators and in freshwater and marine prey, gathered from four European countries. Generic sample preparation protocols for the extraction of CECs with a broad range of physicochemical properties and the purification of the extracts were used. The analysis was performed utilizing liquid (LC) chromatography coupled to high resolution mass spectrometry (HRMS), while the acquired chromatograms were screened for the presence of more than 2,200 CECs through wide-scope target analysis. In total, 145 CECs were determined in the apex predator and their prey samples belonging in different categories, such as pharmaceuticals, plant protection products, per- and polyfluoroalkyl substances, their metabolites and transformation products. Higher concentration levels were measured in predators compared to prey, suggesting that biomagnification of chemicals through the food chain occurs. The compounds were prioritized for further regulatory risk assessment based on their frequency of detection and their concentration levels. The majority of the prioritized CECs were lipophilic, although the presence of more polar contaminants should not be neglected. This indicates that holistic analytical approaches are required to fully characterize the chemical universe of biota samples. Therefore, the present survey is an attempt to systematically investigate the presence of thousands of chemicals at a European level, aiming to use these data for better chemicals management and contribute to EU Zero Pollution Ambition. © 2022 The Author
A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer.
No full textBACKGROUND: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. OBJECTIVE: We aimed to develop alternative dosing regimens to reduce drug expenses. METHODS: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. RESULTS: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. CONCLUSIONS: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice
A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer
No full textBackgroundExpensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide.ObjectiveWe aimed to develop alternative dosing regimens to reduce drug expenses.MethodsWe developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development.ResultsWe found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure.ConclusionsDosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice
Conventional and deep-litter pig production systems: the effects on fat deposition and distribution in growing female large white X landrace pigs
No full textMinimising variability in carcass quality to better meet market specifications is a priority for Australian pig producers, however issues with variability in carcass fat distribution have recently been raised, particularly in the belly primal. There has been a rapid increase in the use of low-cost, deep-litter (DL) housing systems in Australia over the past 15 years for rearing pigs. The inherent differences between the physical, thermal, and social environments of conventional (C) and DL production systems may well alter the growth path of the pig and subsequently alter fat metabolism and hence fat deposition and distribution. The general industry view is that pigs finished in DL housing are fatter and grow less efficiently than pigs finished in C housing, however contrasting carcass and growth performance results have been reported between housing systems. It is likely that the different housing environments affect the maintenance energy requirements of the growing pig, thereby affecting the availability of substrates for fat deposition and/or the requirements for fat mobilisation. Hence, raising pigs in C and/or DL production systems was identified as a likely contributor to variability in carcass fat distribution via the effects of the disparate environments on fat metabolism.
The overall purpose of this thesis was to establish the effect of keeping pigs in C and/or DL housing systems on fat metabolism, and therefore fat deposition in the growing pig and fat distribution in the finished carcass. Industry considers that finishing pigs in C facilities allows greater flexibility in feeding and marketing decisions, allowing growth efficiency and backfat to be managed more effectively than in a DL system. Therefore an aspect of this thesis was to also examine the effects of an alternative management strategy, raising pigs in a combination of DL and C housing, on growth performance and fat deposition and distribution in the carcass. The presence of straw bedding is a major difference between C and DL housing systems. This was identified as a probable contributor to the differences in growth performance and carcass fat distribution found between pigs raised in the different housing systems, via its thermal properties and/or the ingestion of the straw on pig growth.
Experiment 1a and 1b were designed to test the hypothesis that the growth path differs for pigs raised in C and DL housing systems, affecting biochemical indicators of fat metabolism and therefore fat accretion and distribution in the carcass. The study was conducted as a serial slaughter of pigs housed in C and DL systems allowing the pattern of fat accretion, and therefore the distribution of fat in the carcass, to be determined from 15-185 kg live weight (LW). The results confirmed the hypothesis that the growth path, fat accretion and fat distribution in the carcass differed for pigs raised in C and DL housing systems.
In Experiment 1a, elevated lipogenic enzyme activities, higher percentages of saturated fatty acids (SFA) and higher concentrations of plasma glucose and lactate indicated lipogenesis was elevated in C pigs to 13 weeks of age, compared to young DL pigs, suggesting that fat accretion was higher in young C pigs. At 24 weeks of age however there was a shift in lipogenic enzyme activities, the percentage of SFA in backfat and the concentration of plasma glucose were higher in DL-housed pigs than C-housed pigs, indicating higher rates of lipogenesis. Elevated concentrations of plasma non-esterified fatty acids (NEFA) and glycerol in DL pigs indicated that lipolysis, or fat mobilisation, was higher in DL-housed pigs for the entire growth period. The results from Experiment 1b clearly indicated that during early growth, C pigs grew faster than DL pigs (0.71 vs 0.66 kg/day, P less then/= 0.05) and were heavier between 8-23 weeks of age (P less then/= 0.05). Therefore in conjunction with the results of Experiment 1a, it was expected that you ng C pigs would be fatter than DL pigs of the same age. However, dissection indicated no treatment differences in total carcass composition, although there was an effect of housing on carcass fat distribution with a trend (P=0.087) for a lower ratio of fat:lean in the belly primal of DL pigs compared to C pigs at 13 weeks of age. After 20 weeks of age however, growth rates were similar for pigs in both housing treatments and by 26 weeks of age there were no treatment differences in live weight (LW) but the rate of fat accretion in DL pigs, particularly in the loin and belly primals, increased rapidly. Differences in the thermal environments of C and DL housing, and therefore differences in the energy demand for thermoregulation, were likely to have contributed to the differences measured in lipogenesis, growth performance and carcass fat distribution.
Experiment 2a and 2b tested the hypothesis that moving pigs from DL to C housing for finishing would improve overall growth performance and reduce carcass fatness compared to pigs raised in wean-to-finish DL housing. The biochemical measurements indicated few differences in the rate of lipogenesis between 13-week-old C and DL pigs. However, and in agreement with the findings from Experiment 1a, elevated plasma NEFA concentrations in DL pigs suggested higher rates of lipolysis. Up to 13 weeks of age, pigs in the DL housing system grew faster than C pigs, however similar to the findings of Experiment 1b, DL pigs were less efficient. In addition, P2 backfat depth was less in DL pigs, indicating they were leaner than C pigs, and though not reflected in total carcass composition, again there was an effect of housing on fat distribution. The move to an unfamiliar housing environment affected growth performance, reduced enzyme activity in backfat and the ratio of SFA in belly fat, suggesting these pigs had lower rates of lipogenesis. However in contrast to Experiment 1a, where lipogenesis was higher in older DL pigs compared to older C pigs, pigs finished in the DL housing had a trend for lower enzyme activity in belly fat (P=0.063), suggesting lower rates of lipogenesis, and higher plasma glycerol concentrations, suggesting a higher level of lipolysis compared to C-finished pigs. The carcass composition data (Experiment 2b) found that though there were no differences indicated by differences in P2 depth, there was a strong trend (P=0.057) for DL-finished pigs to have 2-6% less fat in the carcass as a result of significantly less fat in the shoulder (15% vs 17%) and belly (29% vs 33%) primals compared to C-finished pigs. The difference in belly primal composition was a reflection of the lower enzyme activities in belly fat and higher plasma glycerol concentrations in DL finished pigs. The results suggest that the type of housing during the finishing growth period has a greater impact on fat accretion and carcass composi ion than the type of housing during the grower period, or changing housing environment during growth. However, changing housing environment at 13 weeks of age affected growth, where there was a temporary reduction in daily LW gain, and therefore significantly lower (P less then/= 0.001) LW at slaughter (117 kg LW), compared to pigs that had remained in C or DL housing from wean-to-finish (123 kg LW). Moving pigs from DL to C housing to control carcass fat and improve growth performance compared to pigs grown wean-to-finish in DL housing, was not successful, and had a negative impact on performance and carcass quality by reducing growth efficiency and LW and increasing carcass fatness. The results also showed that contrary to the industry view that DL raised pigs are fatter, pigs in this experiment finished in DL housing had a lower fat:lean ratio in the carcass than pigs finished in the C system (P less then/= 0.05).
The effects of straw on growth performance and carcass composition were evaluated in Experiment 3a and 3b by including straw in the grower and finisher diets (St+) and/or providing straw bedding (Bed+) to C-housed pigs. The experiment tested the hypothesis that the presence of straw alters the growth paths of pigs, affecting fat distribution in the carcass. Straw, as bedding and in the diet, affected pig growth paths and altered carcass fat distribution and, consistent with the findings for DL pigs in Experiments 1b and 2b, there was a trend for pigs with access to straw to have less fat in the belly (P=0.072).
Elevated activity of key enzymes involved in lipogenesis, measured in Experiment 3a in belly fat and backfat from pigs fed the St+ diet, and a higher ratio of SFA in belly fat of pigs housed on concrete without straw bedding, suggested that in this experiment straw ingestion increased lipogenesis in belly fat and backfat of the growing pig, whilst straw bedding reduced lipogenesis in belly fat. Experiment 3b demonstrated an additive effect of straw on growth where average LW at slaughter for pigs without access to straw was significantly lower (110 kg), compared to pigs with access to one source of straw either via the diet or bedding (115 and 114 kg LW respectively), and pigs that had two sources of straw available (119 kg LW) (P less then/= 0.05). Although LW differed between treatments there were no differences in total carcass fat (P>0.10), yet there was an effect of straw on fat distribution. Pigs with access to straw had a lower ratio of fat and a higher ratio of lean tissue in the belly primal (P=0.072) compared to pigs that did not have straw. The effect of straw ingestion on lipogenesis and fat deposition may have occurred via the effects of dietary fibre (DF) on the dilution of dietary energy density. Pigs were able to compensate for the energy/nutrient dilution by increasing VFI and therefore growth was not affected, however fat acts as an insulator, and localised differences in fat distribution may have been related to increased heat production (HP) from the digestion of greater volumes of feed. In response, fat deposition may have been directed away from the belly location in order to facilitate heat loss. Floor type may have also affected fat distribution via differences in thermal conductivity. Straw has a lower thermal conductivity than concrete, hence pigs housed on concrete flooring may have a greater requirement for fat in the belly to reduce conductive heat loss. Results from Experiment 3a and 3b provided evidence that pigs housed on bedding consume straw in sufficient quantities. Pigs fed the straw diet had significantly higher concentrations of plasma acetate than pigs fed the control diet (P less then/= 0.001), and there was a trend for pigs housed on straw bedding to have higher levels than pigs without access to straw. An increase in plasma acetate can indicate increased microbial activity in gut, which occurs in response to higher levels of DF. In addition, pigs bedded on straw had higher gastrointestinal tract weights, which can also indicate higher levels of DF intake.
Regression analyses of data across experiments showed that P2 backfat depth, the primary carcass composition prediction tool, accounted for less than 50% of the variation in percent carcass fat (R2=0.41). Furthermore, across experiments, P2 accounted for very little of the variability in percent belly fat (R2=0.01). These results highlight the inconsistency of P2 depth as a reliable indicator of carcass composition and the need for the development of additional criteria to be used in the selection of carcasses for specific markets as the composition of the belly primal was not indicated by the current carcass measurement system.
From the results obtained in this thesis, it was proposed that:
1) The growth path of pigs is altered by the housing system in which they are reared and the more variable ambient temperature of the DL housing system would increase the energy requirement of young pigs for thermoregulation. As a consequence of the altered growth paths, fat metabolism differs for pigs raised in DL and C production systems. Lower rates of lipogenesis may occur in young DL pigs compared to C pigs and this can change as pigs grow, however fat mobilisation remains higher in DL pigs during growth.
2) Differences in the rate of lipogenesis, indicated by the biochemical measures, were generally not reflected in total carcass composition, however there were differences in carcass fat distribution where pigs raised in DL systems consistently had less fat in the belly primal. Rearing environment may provide an additional criterion when selecting carcasses for specific markets where variability in belly composition is an issue.
3) Pig raised in the DL environment are not always fatter than pigs housed in C facilities, and moving pigs from one housing environment to another during the growing-finishing period disrupts the growth path reducing growth performance and can increase carcass fatness.
4) Straw bedding, via ingestion and via its physical thermal properties, affects pig growth and fat distribution and may explain in-part the differences in pig growth performance and carcass quality found between C and DL housing systems
