Effect of calcium hydroxide and sodium hydroxide with different doses on the vigor of the seeds in different storage times.
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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History, Design, Manufacturing, and Applications",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tThe development of RNA therapeutics has been an intense journey, with numerous stories of success and failure. The potential, and suitability, of recently discovered RNAs (for therapeutics), stemmed from several Nobel Prize-winning discoveries. Currently, novel RNA drugs are entering clinical trials almost daily. RNA therapeutics are chemically synthesized biomolecules with broad clinical applications, ranging from correcting inherited mutations, to treating cancer, and chronic conditions, improving organ transplant outcomes, and infectious disease prophylaxes.
\r\n\tRNA therapies evolved as profitable and widely applicable individualized treatment solutions. Moreover, RNA-based therapeutic vaccines (e.g., against SARS-CoV-2 infection) have been proven to be safe and effective, and several of them are approved by the United States Food and Drug Administration (FDA).
\r\n\tThis book aims to present distinct classes of RNA therapeutics, ranging from single-stranded antisense oligonucleotides (ASOs), and subclasses of RNA interferences (miRNAs and other RNAi), to in vitro transcribed mRNAs and RNA vaccines. Also, it will present some of the challenges in RNA drug engineering, delivery, and specificity. Additionally, the improvement of pharmacological effectiveness will be discussed. Monumental breakthroughs in molecular biology, computational chemistry, bioinformatics, and individualized genomics, which undoubtedly propelled RNA therapeutics through the commercialization stage, will also be examined in this book.
\r\n\tRNA therapeutics have had a significant impact on medicine, the economy, and overall public health; they are becoming prescription drugs, and this holds great promise for modernizing healthcare.
Fruit trees play an important role in human nutrition; and among these highlights, the papaya, this is a crop of tropical climate, widely appreciated for being one of the few fruit that provide continuous production throughout the year after the start of fruiting, to possess fruits with a high nutritional value, and to achieve high yields; generating good income to the families dedicated to their cultivation, due to the high prices that reaches in the market [1].
\nThe world production of papaya occurs in more than 60 countries, according to FAO, for the year 2010, a production of 11,568,346 tons of the fruit was registered, with the main producing countries of the highest to lowest volume: India, Brazil, Indonesia, Nigeria, Mexico, Ethiopia, Colombia, Thailand, and Guatemala [3].
\nAs a crop is an important source of employment, has a good yield, earliness to enter into production, and guarantees staggered crops throughout the year. Despite all these advantages, it does not reach the maximum productive potential, this is due in large measure to the problematic that it manifests in terms of the quality of seed [4]. Is consider one of the tropical fruits more appreciated for fresh consumption and for industrialization [5]. In Mexico like in Cuba, Maradol variety is the more cultivated, is a Cuban variety.
\nDifferent varieties of papaya are commercially propagated through seed an easy management and low cost, without taking into account the heterogeneity caused by crossed polinization [5].
\nIn the sowing of papaya, it is best to use freshly harvested seeds, because while increasing the storage time of the seed, the germination rate decreases [6]. The majority part of the papaya sowing is done with stored dry seeds, and in this condition, the seed germination is erratic, asynchronous, slow, and incomplete [7], which diminishes the germination percent [5]. The desiccation produces stress in the papaya seeds when the moisture content lowers to 8.0% [8], being the cause of the seed dormancy or metabolic quiescence [9, 10]. In Taiwan, the papaya industry is limited by seed germination rates [11]. This is attributed to the presence of inhibitors as the phenolic compounds in the sarcotesta and seed coat [12, 13], and in some cases, the seeds lack embryos [6].
\nThe seed is enclosed in a gelatinous sarcotesta (aril or seed coat), which is formed from the outer integument [14]. The sarcotesta can delay germination, and also dormancy is observed in seeds from which the aril has been removed [15].
\nPapaya, like many plants, presents as one of its main problems in its reproduction, the dormancy of the seed which influences the quality of it; because by reaching its maximum point of maturity, it initiates a period of latency produced by internal and external factors. It is normally interrupted when the natural conditions suitable for germination are present or when treatments are used that help to propitiate these ideal conditions and increase the percentages of germination [16], but in vitro conditions favored germination of papaya more than in vivo environment [17].
\nThe seed of papaya is characterized by being bitegumented, since the internal tegument originates the tegumen and the external one to the testa, which is multiplicative up to 60 layers and 3 distinctive strata: endotesta, mesotesta, and exotesta (sarcotesta). This last one of semipermeable consistency, high humidity and concentrate phenolic compounds that, as a whole, induce latency. This causes the inhibition of fluid and gas exchange, delayed dehydration and colonization of pathogenic microorganisms. In [18] are mentioned others researchers who investigated this problem [19, 20].
\nOne of the ways to break the latency of the seeds and make them have a good quality overall, increasing the percentages of germination is using the different methods of scarification.
\nThe methods of scarification include physical, mechanical, and biological treatments such as dry heat, the rupture of the testa, the soaking in water, and chemical solutions that promote the germination of the seeds, where any treatment that destroys or reduces the impermeability is called scarification, so in some cases, it is only enough to destroy a single point of the cover to produce the imbibitions and exchange of gases and thus initiate the germination [21].
\nApparently, latency is a survival mechanism in the presence of certain climatic conditions: very low temperatures, alternations of dry and humid times, and desert climates. The exact causes of the latency phenomenon are unknown, and on the other hand, when the latency is due to testa conditions, the lethargy ends at the moment that it cracks or weakens by mechanical or chemical actions or by effect of the environment [22, 23].
\nDifferent seed treatments to promote germination and to reduce germination time are mentioned in [24], sowing seeds and at warm temperatures, exposing dry seeds to 10°C prior to sowing, drying seeds and soaking seeds in distilled water, potassium nitrate, thiourea, sodium thiosulfate, tannic acid or ferulic acid. The same authors described contradictory results using gibberellins on papaya seed germination. But in your research, they demonstrated that dehydration to 5.3% or 6.9% and 6.8% moisture content, followed by exposure to subzero temperatures and treatment with GA3, were the most favorable combined treatments to enhance papaya seed germination.
\nThe used of smoke water on seed germination and seedling growth of papaya, cultivar Tainung No. 2 consistently and significantly increased the percentage of nitrogen in roots and shoots and significantly increased the percentage of magnesium in shoots. In these experiments, smoke-water showed potent germination promotion at low concentrations and promoted multiple growth attributes such as chlorophyll content and seedling vigor index at all concentrations in papaya seedling production [11].
\nPregerminative treatments are used to break the latency status of the seeds. In [25] are mentioned stratification and scarification. Scarification is any process that breaks, scratches, mechanically alters or softens the covers of the seeds to make them permeable to water and gases.
\nSeed scarification methods have been developed and modified over time to make these more practical and effective. Important methods of seed scarification include heat, freeze–thaw, mechanical, and acid scarification [16].
\nIn the scientific literature, some types of scarification are described, such as mechanical [26, 27, 28], physical [29, 30, 31], chemical [32, 33], and biological. Mechanical, physical, and biological scarification have disadvantages in relation to chemical scarification, because they require more time, are laborious and inadequate to condition large quantities of seed; while chemical scarification still requires more research [18], especially with calcium hydroxide.
\nThere are chemical substances used to scarify seeds, among the most used are the sulfuric acid [34], sodium hydroxide, and hydrochloric acid [7, 18, 20, 31]. The positive effect of the use of NaOH in the benefit of papaya seed is that simulates natural degradation of sarcotesta and improves the conditions of the seed, so it is a viable alternative for use in conditioning seed [18]. Other results have been demonstrated that the combination of NaOH treatment and stratification is an effective practice to break
Chemistry scarification is considered as one of the most effective scarification methods used for seed scarification. Sulfur acid is the most popular and effective chemical product for acid scarification. The effectiveness of acid scarification depends on concentration of acid duration of scarification and species and cultivars used [16, 36].
\nTraditionally, it has been used to separate the mucilage from the papaya ferment the seeds in water at different time intervals and the sunny one for 2 or 3 h [37].
\nThe objective of the research was to evaluate the scarifying effect of calcium hydroxide on the germination and vigor quality of papaya seeds, Maradol variety.
\nThe experiment was carried out in the Laboratory of Seed Test of the plant of Benefit Manuel Espinosa Ramírez of the business unit of seeds base Granma, belonging to the company producer and marketer of seeds, using seed of papaya ‘Red Maradol’, collected in areas of the Experimental Station Jucaibama of the Agricultural Research Institute Jorge Dimitrov, Bayamo, Granma province.
\nThe sample consisted of 60 randomly selected fruits of hermaphroditic plants in a commercial production lot of approximately 1 ha (2222 plants), showing commercial maturity (two strips), of homogeneous size (±2 kg). The seeds were extracted, and the batch was homogenized; 200 g of fresh dough were deposited with 500 ml plastic flasks representing each experimental unit.
\nThe treatments were composed of the solution of calcium hydroxide (CaOH2) at three doses (60, 80, and 120 g l-1 of water) by dipping the seed for a period of 24 h, the standardized sodium hydroxide (NaOH) at 25% with a 15-min immersion time, for a total of four treatments plus the control and six replicates. The control consisted in fermenting in running water the seed for 24 h.
\nTo eliminate the sarcotesta (aril), the seeds were rubbed between two jute cloths where the time needed to remove all the aril of the material was evaluated, being the optimal time to use of 15 s for each treatment given the amount of material to process. Immediately, they were rinsed three times with running water, spread over a sieve in the shade and at room temperature (28 ± 1°C) for drying for 48 h.
\nThe physical quality of the seed was determined by the effectiveness of the product, physical appearance, and mechanical damage within 3 days of the treatment, compared to the control; the physiological quality was determined by the germination percentage 7 days after sowing (vigor), being valued by the germination rate [38], and 28 days for final germination (as indicated in the germination standard, with the method in sand). The seed was soaked for a term of 24 h and placed in previously disinfested aluminum trays at a temperature of 100°C.
\nThe incubation was carried out in the germinating chamber Paul Polikeit, Model HALLE S. A, with 80% of relative humidity, 40 ± 2°C of temperature and natural light; for the sanitary quality, it was determined by assembling all the treatments with the method between paper (BP), evaluating by observing the evidences of the development of microflora on the seed, during the germination test.
\nTo carry out this test, three repetitions of 25 seeds were used by extraction, it was put to incubated in water the seeds for a time of 24 h, after the time elapsed, each seed was sectioned in longitudinal form leaving the cotyledons visible placed in culture tubes wrapped with aluminum foil adding a solution of 2, 3.5-triphenyl chloride tetrazolium to 1%, and the tubes were placed in an incubator at 35 ± 1°C for a time of 2 h.
\nThe experimental design used was completely randomized with bifactorial arrangement and six replicates. The variables assessed were vigor (vigor, 120, 240, and 360 days of conservation at 4–8°C, in percent); germination (germination, 120, 240, and 360 days of conservation at 4–8°C, in percent); the time needed to eliminate aril (s), mechanical damage, MD (%), and abnormal plants, AP (%), according to ISTA Methodology [38].
\nThe data for each measured variable were statistically processed to check compliance with the normal distribution of the data (Kolmogorov-Smirnov test) and the homogeneity of the variances (Bartlett test). These two premises of the analysis of variance were not met, even after testing several data transformation equations, so we proceeded to the application of nonparametric variance analysis through Kruskal-Wallis, to demonstrate the existence or not of variability between treatments with a probability level of 0.05. The averages (aver.) of the treatments, the standard deviation (sd) of the mean, and the significance are shown. The multiple comparisons between treatments were made through the differences between the averages of the ranges [39].
\nWe also performed analysis of partial correlations between variables with the use of Spearman correlating coefficient, with the aim of determining the existence of linear relationship between selected variables. Those variables that could have a direct or inverse relationship were selected in relation to the vigor and germination in their different times used as the aril, the mechanical damages, and the percentage of abnormal seeds.
\nStatistical processing was carried out with the use of statistical packages MINITAB 13 [40] for the test of homogeneity of variances and Infostat 2017 [41] for the rest of the statistical analyses.
\nSignificant differences were found between the different treatments in the vigor of the seeds (Table 1). The highest level of vigor of the seed was due to the use of calcium hydroxide, more than sodium hydroxide and fermentation. This tendency was maintained during the different storage times of the seeds at a constant temperature. Significant although not shown statistically, there is evidence of a decrease in the seeds vigor for all the evaluated treatments by increasing the conservation time of papaya seeds, which suggests that it is more efficient to apply calcium hydroxide in order to improve the response of papaya seeds with a minimum storage time.
\nVigor (%) | \n|||||
---|---|---|---|---|---|
Compound | \nDose | \n0 days | \n120 days | \n240 days | \n360 days | \n
Aver. ± SD | \nAver. ± SD | \nAver. ± SD | \nAver. ± SD | \n||
Ca(OH)2 | \n60 g l−1 | \n80.7ab ± 2.8 | \n83.7a ± 2.7 | \n77.3b ± 2.3 | \n71.7ab ± 5.7 | \n
Ca(OH)2 | \n80 g l−1 | \n81.7ab ± 1.6 | \n81.2ab ± 1.2 | \n79.3ab ± 2.3 | \n60.0bc ± 6.8 | \n
Ca(OH)2 | \n100 g l−1 | \n89.3a ± 1.2 | \n82.3a ± 2.2 | \n82.3a ± 1.7 | \n75.7a ± 3.6 | \n
NaOH | \n25 g l−1 | \n50.3c ± 4.2 | \n42.7c ± 3.7 | \n26.5c ± 3.4 | \n6.7c ± 0.5 | \n
Fermentation \n | \n75.3bc ± 1.9 | \n75.8bc ± 3.4 | \n73.5bc ± 3.5 | \n71.7ab ± 4.8 | \n
Effect of calcium hydroxide and sodium hydroxide with different doses on the vigor of the seeds in different storage times.
Different letters indicate significant differences to p ≤ 0.05 through the differences between the average of the ranges.
The variability in the response of calcium hydroxide could be a consequence of the fact that some seeds within the same batch have a more persistent dormancy than others and that small and large seeds can be found in the same batch [42].
\nSodium hydroxide reached lower percentages, even less than 60%, which is the minimum value established for Cuba for this crop [43, 44].
\nThe physiological quality of the papaya seed is characterized by a high sensitivity to several factors with respect to germination and vigor, considering that there are integrating elements of great importance at the plantation level [45].
\nFor the germination (Table 2), the application of calcium hydroxide obtained the best results, with percentages over the 80% in comparison with the rest of the treatments. Germination was more affected when the seeds were treated with sodium hydroxide and to the extent that the storage time of the seed was increased. Like the vigor, the germination percentage decreases in the treatments when the conservation time increased.
\nGermination (%) | \n|||||
---|---|---|---|---|---|
Compound | \nDose | \n0 days | \n120 days | \n240 days | \n360 days | \n
Aver. ± SD | \nAver. ± SD | \nAver. ± SD | \nAver. ± SD | \n||
Ca(OH)2 | \n60 g l−1 | \n88.0ab ± 2.18 | \n87.3b ± 1.6 | \n80.2bc ± 1.73 | \n89.3ab ± 6.6 | \n
Ca(OH)2 | \n80 g l−1 | \n89.0ab ± 1.9 | \n89.0ab ± 1.6 | \n81.8ab ± 1.2 | \n70.5bc ± 8.2 | \n
Ca(OH)2 | \n100 g l−1 | \n94.0a ± 2.9 | \n92.3a ± 2.0 | \n85.3a ± 1.8 | \n88.8a ± 4.3 | \n
NaOH | \n25 g l−1 | \n65.3c ± 4.2 | \n56.0c ± 3.2 | \n42.0d ± 3.0 | \n15.5c ± 3.1 | \n
Fermentation \n | \n83.7bc ± 2.3 | \n83.7bc ± 2.7 | \n76.3cd ± 2.9 | \n84.3ab ± 6.08 | \n
Effect of calcium hydroxide and sodium hydroxide with different doses in germination percentage of seeds.
Different letters indicate significant differences to p ≤ 0.05 through the differences between the average of the ranges.
Physiologically, these results could be interpreted as a sequence of events of deterioration that begins with problems of functionality in the seminal membranes, which causes an excessive flow of cellular constituents, evidenced this by the high absorbance values and consequent loss of metabolites, the magnitude of which can restrict the germinative process [46].
\nCold stored papaya seeds maintained significantly higher germination and better seedling vigor than the room stored seeds. With the increase in the duration of storage seed germination decreased after 20 mo. at room temperature, it declined marginally during the same period when kept in cold storage. Irrespective of the storage conditions, seeds kept in sealed polythene bags or plastic bottles had better germination and seedling vigor than those on paper and cloth bags. Shoot length and dry weight decreased significantly with the increase in the duration of storage. Viability of papaya seeds can be maintained considerably at room temperature up to 8 mo. by storing the seed in sealed, preferably airtight, polythene bags or plastic bottles. Cold storage using polythene bags or plastic bottle is recommended [47].
\nThe storage conditions are very important. According to the classification of seed storage behavior, the papaya seed is classified as recalcitrant seed [48], others in intermediate seed [49]. In storage behavior ambient conditions, the papaya seeds survive for a short period of time [50] and are considered intermediate between recalcitrant and orthodox attribute and deteriorate rapidly at higher storage temperatures and relative humidity. Fresh seeds give higher germination rate and seedling vigor that will decline with increasing the storage time [51] and consider that the best conditions for papaya seed storage is when containing 6.0% moisture and stored at 0°C gave higher percentage of germination, lower dormancy, and seed death.
\nIn [18], the treatment that most affected the germination was the application of sodium hydroxide and the higher incidence of microorganisms, with high percentages of plants affected by fungi, which remained even below the germination approved for marketing, which requires, more than 60% [43].
\nIn [52], described some pre-sowing treatments with the finality of increase the germination, like preconditioned papaya seed at 24°C before transfer to 32°C, soaked in KNO3 for 30 min, soaking in gibberellic acid (GA3; 200 ppm) for 24 h resulted in highest germination percentage in soil compared to α-naphthalene acetic acid (NAA) and KNO3 treatment, and using a protocol of sterilization and germination of papaya seeds in response to light emitting diodes and got 100% of sterilization and 100% of germination.
\nThe efficiency of the different scarification methods has been demonstrated in several investigations to favor the germinative process. In [53] were evaluated several methods of scarification of pacain seeds (
With chemical scarification methods also obtained positive results [54], and verified germination percentages of 97 and 94%, respectively, in seeds of
The treatments used release the aril at different time intervals and there are differences between them in relation to the mechanical damage and the quantity of abnormal seeds of the Maradol variety (Table 3). The best results were obtained when calcium hydroxide was applied at the 100 l−1 dose and with sodium hydroxide. Those compounds only needed an average time of 12 s to achieve an efficiency in the detachment of the aril, while with the application of the control dose, the worst results were obtained, with an average of 38 s that in some cases reached reaching more than 420 s to achieve the release of the aril, so that with this result, it is inferred that to work 25 kg of wet seeds, it would take approximately 38 min if treated with sodium hydroxide or calcium hydroxide in 100 l dose and approximately 106 min for the case fermented only with water.
\nCompound | \nDose | \nAril (s) | \nMD (%) | \nAP (%) | \n
---|---|---|---|---|
Aver. ± SD | \nAver. ± SD | \nAver. ± SD | \n||
Ca(OH)2 | \n60 g l−1 | \n21.2cd ± 1.3 | \n1.0a ± 0.9 | \n1.5ab ± 1.5 | \n
Ca(OH)2 | \n80 g l−1 | \n17.7cd ± 2.5 | \n1.0a ± 0.9 | \n0.7a ± 1.0 | \n
Ca(OH)2 | \n100 g l−1 | \n13.3ab ± 1.4 | \n0.5a ± 0.6 | \n0.4a ± 0.7 | \n
NaOH | \n25 g l−1 | \n12.0a ± 0.9 | \n0.5a ± 0.2 | \n3.3b ± 1.0 | \n
Fermentation \n | \n37.7d ± 6.3 | \n9.2b ± 1.2 | \n0.8a ± 0.9 | \n
Effect of calcium hydroxide and sodium hydroxide with different doses in the time (s) of detachment of the seed’s aril.
Different letters indicate significant differences to p ≤ 0.05 through the differences between the average of the ranges.
When carrying out an essay [55], with different methods to improve the germination of four forage shrubs legumes [Tagasaste (
Refs. [7, 20] observed a negative effect on the papaya germination due to the presence in the aril or sarcotesta of inhibitory substances. It is also said that the marked decrease in germination, in the presence of sarcotesta is due to the low oxygenation of the seeds, which is why it is recommended to remove it. Likewise, in a study carried out in Honduras with seeds of the papaya, Maradol variety, higher percentages of germination were obtained with freshly harvested and oared seeds (83%), while fresh seeds with burned arils showed a lower percentage of germination, with 75% [56].
\nSimilar results presented by [18, 20] which treated seeds with very corrosive products not only the germination is affected, but that several plants emerged with problems fundamentally in the radicle and hypocotyl, assuming the influence of other factors such as fluctuation in the moisture of the seed in the time of conservation.
\nThe variables that were selected for the multiple correlation analyses (Table 4) showed that the release of aril seed correlated significantly with germination and vigor 360 days, positively and in a mean size. No correlations were found between this variable and the rest of the values of germination and vigor evaluated. Candiani et al. [57] concluded that the germination of
Correlations analysis | \n|||
---|---|---|---|
\n | Aril | \nMD | \nAdnor | \n
Ger 0 | \n0.13 ns | \n0.07 ns | \n−0.74* | \n
Ger120 | \n0.24 ns | \n0.15 ns | \n−0.71* | \n
Ger240 | \n0.25 ns | \n0.18 ns | \n−0.72* | \n
Ger360 | \n0.46* | \n0.34 ns | \n−0.70* | \n
Vigor | \n0.13 ns | \n0.08 ns | \n−0.73* | \n
Vigor120 | \n0.28 ns | \n0.19 ns | \n−0.70* | \n
Vigor240 | \n0.30 ns | \n0.22 ns | \n−0.69* | \n
Vigor360 | \n0.46* | \n0.34 ns | \n−0.70* | \n
Spearman correlations coefficient between variables.
Indicate significant differences to p ≤ 0.005.
Ger is germination, MD is mechanical damage, and adnor is adnormal plants.
The mechanical damage caused to the seeds during this process in this experiment did not correlate with the different levels of germination and vigor that were studied; however, the percentages of abnormal plants in the different time intervals evaluated showed a significant correlation, with medium to high values, but inverse and indicates that as the percentage of abnormal plants increases in a seed lot, the number of seeds germinates decreases and the vigor. Germination vigor is driven by the ability of the plant embryo, embedded within the seed, to resume its metabolic activity in a coordinated and sequential manner.
\nWas analyzed the vigor tests on lettuce (
In studies [62] about studied the correlations of seed germination percent of two sweet corn hybrids (
The germination vigor depends on multiple biochemical and molecular variables. Their characterization is expected to deliver new markers of seed quality that can be used in breeding programs and/or in biotechnological approaches to improve crop yields [63].
\nCalcium hydroxide has great potential to be used as biocide in agriculture, because it has the advantage of not being phytotoxic, is economic and easy to use and is harmless to the environment and to humans. Decreased Ca levels in the nutrient medium reduced soybean leaf dry matter during seed fill, seed production, seed Ca concentration, and seed germination and increased the incidence of seedling disorders such as watery hypocotyl and epicotyl necrosis [64].
\nIn [65] performed standard germination tests, germination and growth rate, accelerated aging, electrical conductivity, respiration rate and ATP content, to evaluate the vigor of the seeds of
Some researches [66] showed that seed size is an important factor for germination and seedling vigor, establishing that larger seeds produce more vigorous seedlings but with slower emergence. So it can be argued that by using the largest scarified seeds that we have, we can help considerably to decrease the percent of abnormal plants and at the same time increase the vigor and the percentage of germination, variables evaluated in the present investigation.
\nTo correlate characters related to seed germination, is important to investigate the effects of environmental factors prevailing during seed maturation under controlled conditions to understand exact reasons for unusual seed dormancy and germination requirements, for example, the germination of
Seed germination tests assess the ability of the seed to produce a healthy plant when placed under favorable environmental conditions. Germination tests are conducted for a prescribed time period under laboratory conditions that assure optimum moisture, temperature, and light. Unfortunately, these conditions are seldom encountered in the field, and field emergence may be overestimated by standard germination tests. Seed lots that have low germination also are less vigorous due to seed deterioration. As seeds deteriorate, loss of vigor precedes loss of viability, so seeds with low germination usually will be less vigorous. Hence, in seed lots with poor germination, those seeds that do germinate often produce weaker seedlings with reduced yield potential. However, some species (such as many native grasses) have inherently low germination potential and cannot be assumed to have poor vigor due to low germination. Seed vigor usually cannot be assessed by the consumer. Germination is a good indicator of seed vigor [63, 68].
\nUsing efficient methods to scarify papaya seeds can increase the germination percentages of seeds, only if there is good control of environmental factors, because papaya seed germination is affected by light, temperature, oxygen, pH, and the moisture of the substrate [7].
\nIt is necessary to conduct researches about the biometric and morphological characteristics of fruit and seeds, aiming at the maximum germination capacity and seed vigor [69], because biometric studies of seeds and their phenotypical correlations allow the quantitative evaluation of a character’s relevance in relation to another [70]. It continues to investigate the correlations between the different indicators that can characterize the quality of the seeds. In adaptive correlations between seed size and germination time [71], present a model for the coevolution of seed size and germination time within a season when both affect the ability of the seedlings to compete for space and show that even in the absence of a morphological or physiological constraint between the two traits, a correlation between seed size and germination time is nevertheless likely to evolve.
\nSeed germination is a complex process and we need to understand the underlying molecular, hormonal, and mechanical aspects [72]. The environment during seed production has major impacts on the behavior of progeny seeds [73]. For that reason, the seed biology is considered the principal research topic for food security take into consideration the climate change [72].
\nNowadays, there are advances in the propagation of papaya by biotechnological methods. Efficient micropropagation of papaya has become crucial for the multiplication of specific sex types of papaya and in the application of genetic transformation technologies. Significant progress has been achieved using organogenesis and somatic embryogenesis as the shoot tip, axillary bud and single node culture, organogenesis, anther and ovule culture, and regeneration from protoplasts, callus induction and somatic embryogenesis and the mass propagation by ex vitro rooting and acclimatation [74].
\nIn natural conditions, the germination of papaya seeds has difficult by the presence of aril (sarcotesta) that become in a physical barrier which limits the diffusion of water and gases into the seeds and by the effect of phytohormones which preventing germination of seeds, causing dormancy, limiting the development of the embryos and causes a low and variable germination affecting the final percentage. This problem can be solved with the scarification of papaya seed. The results of this research showed that the dormancy by the presence of aril is produced in the papaya seed can be broken with the use of NaOH; but higher results were achieved with the use of calcium hydroxide, Ca(OH)2. The results suggested that chemical scarification with calcium hydroxide can improve germination percentage and vigor of the papaya seeds, take into account that the seed is considered the major essential input in crop production. If the seed quality parameters (vigor, germination rate) decrease, the yields are affected. The scarification of papaya seeds with the use of calcium hydroxide for its proven effect in this research on the benefit of papaya seeds and easy acquisition and will reduce the costs of seed. But a good germination of the papaya seedlings depends on the many environmental factors and excellent agronomy practice. Finally, the effectiveness of scarification methods could change among cultivars within the papaya specie.
\nBiologic therapies, notably the monoclonal antibodies, changed dramatically the scenario of inflammatory bowel diseases (IBD) treatment in the past years. However, such medications have high costs that can limit patient’s access to them [1, 2, 3]. In 2016, monoclonal antibodies represented only 1% of all biologic medications distributed by the Brazilian Public Health System, but 32% of expenses in biologic products [4]. Additionally, evolving treatment goals for IBD patients aiming deep remission and mucosal healing increased the use of biologics in treatment algorithms [5]. As demand becomes greater and the patents of older biologic therapies are expiring, the interest in marketing comparable versions of the reference products (RP) also increases.
Biosimilars are biologic medications resembling the RP, without clinically significant differences in safety and efficacy. Biosimilars have the potential to expand access to biological therapies due to price competition and cost savings [1, 2, 3]. An analysis elaborated by the Johns Hopkins Bloomberg School of Public Health found that biosimilar price represented 68% of the RP price for infliximab in 2018 in the US and estimated a saving of $407 million to up to $1.4 billion in the same year if full biosimilar substitution of infliximab was supported by all employers who self-insure health coverage [6].
Following the expiration of Remicade® patent, CT-P13 was the first infliximab biosimilar to be approved by European Medicine Agencies (EMA) in 2013 after two clinical trials. The studies PLANETAS and PLANETRA compared CT-P13 to the RP in patients with ankylosing spondylitis and rheumatoid arthritis, respectively [7, 8]. In April 2015, the Brazilian Health Regulatory Agency (ANVISA) approved the first biosimilar of infliximab, Remsima® (Celltrion) [9] and, since then, there are three infliximab and three adalimumab biosimilars approved in Brazil (AMGEVITA™, HYRYMOZ® and Xilbrilada®). Tables 1 and 2 summarize all approved biosimilars from infliximab and adalimumab by FDA, EMA and ANVISA.
Non-proprietary name (NPN) (US) | US | EU | Brazil | Marketing authorization holder (MAH) | Investigational medicinal product (IMP) |
---|---|---|---|---|---|
adalimumab-atto | Amjevita | Amgevita* | Amgevita* | Amgen | ABP501 |
adalimumab-adbm | Cyltezo | — | — | Boehringer Ingelheim | BI695501 |
adalimumab-adaz | Hyrimoz | Hyrimoz* | Hyrimoz* | Sandoz | GP2017 |
adalimumab-bwwd | Hadlima | Imraldi* | — | Samsung Bioepis | SB5 |
adalimumab-fkjp | Hulio | Hulio* | — | Mylan | FKB327 |
adalimumab-afzb | Abrilada | Amsparity | Xilbrilada | Pfizer/Wyeth | PF-06410293 |
— | — | Idacio* | Idacio | Fresenius Kabi | MSB11022 |
Biosimilars for adalimumab approved by health authority. Correct of February 2021.
Marketed.
Non-proprietary name (NPN) (US) | US | EU | Brazil | Marketing authorization holder (MAH) | Investigational medicinal product (IMP) |
---|---|---|---|---|---|
infliximab-abda | Renflexis* | Flixabi* | Renflexis | Samsung | SB2 |
infliximab-qbtx | Ixifi | Zessly1,* | Xilfya* | Pfizer/Sandoz1 | PF-06438179 |
infliximab-axxq | Avsola* | — | Avsola | Amgen | ABP710 |
infliximab-dyyb | Inflectra* | Remsima/Inflectra* | Remsima* | Celltrion | CT-P13 |
Biosimilars for infliximab approved by health authority. Correct of February 2021.
Licensed by Sandoz in EU.
Marketed.
This chapter explores general concepts of biosimilars and their implications in clinical practice in the context of inflammatory bowel diseases (IBD) treatment. We aim to summarize the positions of various scientific associations in the IBD field with respect to biosimilars and provide real-life data regarding their effectiveness and safety in countries where they have been used. In addition, the authors will focus on relevant questions encountered in the clinic, including issues related to switch, biosimilar knowledge among IBD specialists and nocebo effect.
Biosimilar uptake is increasing worldwide and accumulating evidence has been demonstrating the efficacy and safety of these drugs for the treatment of IBD patients [10, 11, 12, 13, 14, 15, 16]. Figure 1 illustrates biosimilars for infliximab and adalimumab in the pipeline.
Biosimilars for infliximab and adalimumab.
However, most data on biosimilars in IBD originate from real-life experience after switching from a reference biologic to a biosimilar [17] and the available randomized controlled studies comparing the reference biologic and biosimilars often had a short-term follow-up [18].
Ye et al. conducted the first randomized, multicenter, double-blind, phase 3 and non-inferiority study evaluating the efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn’s disease (CD). Patients were randomly assigned (1:1:1:1) to receive CT-P13 then CT-P13, CT-P13 then infliximab, infliximab then infliximab or infliximab then CT-P13, with switching occurring at week 30. The primary endpoint was the proportion of patients with a decrease of 70 points or more in the Crohn’s Disease Activity Index (CDAI) at week 6. Response rates were similar between the two groups (CT-P13: 69.4%, CI 95%: 59.9–77.8 vs. IFX: 74.3%, CI 95%: 65.1–82.2), establishing the non-inferiority of CT-P13 in relation to IFX [18]. Accordingly, in a prospective, observational and multicentre study, Gecse et al. evaluated the efficacy, safety and immunogenicity of CT-P13 in the treatment of CD induction (
A recent systematic review and meta-analysis by Queiroz et al. assessed the risk and reasons for drug discontinuation in the IBD population that switched from the originator to biosimilars in real-world studies [20]. A total of 30 observational studies comprising 3594 IBD patients who switched from originator biologics to biosimilar with a mean follow-up period over 6 months and a mean duration of treatment with the originator reported as over 1 year were included. In addition, the reasons for treatment discontinuation were extracted and meta-analyzed. The discontinuation rates after a switch were 8, 14 and 21% after 6, 12, and 24 months, respectively. The main reasons for discontinuation were as follows: increased loss of response (2%), remission (4%), loss of adherence (4%), adverse effects (5%) and loss of response (7%). Quality of evidence varied from low to very low depending on the analyzed outcome. The nocebo effect was explicitly analyzed as a reason for discontinuation in only one study [21], and the frequency of reported subjective adverse events was low. It is important to emphasize that most of the studies included in this review did not disclose important information that could have influenced the results, such as disease activity at the moment of switch and drug trough levels before and after switch. This study raises awareness for the urgent need to conducting prospective studies evaluating long-term outcomes associated with the switch of biological therapy in IBD patients.
In 2015, a task force of three Brazilian medical societies involved in the treatment of immune-mediated diseases (gastroenterology, rheumatology and dermatology) has first issued guidance on the utilization of biosimilars [22]. Since the approval of CT-P13 in Brazil, several IBD societies worldwide have issued position statements regarding the use of biosimilars for the treatment of Crohn’s disease and ulcerative colitis [22, 23, 24, 25, 26]. What is still a huge discussion in the medical literature, indeed, is the switch or transition between biologicals: innovator to biosimilar, biosimilar to innovator and biosimilar to other biosimilar. The main recommendations from different IBD societies are summarized as follows:
GEDIIB (Grupo Brasileiro da Doença Inflamatória Intestinal do Brasil): The Brazilian IBD Study Group advises all members about the entry of biosimilars into the Brazilian pharmaceutical market. The guidelines highlighted some important points regarding the switch between biological drugs, which must be carried out with the consent of both the attending physician and the patient [24]. GEDIIB also acknowledge the effectiveness and safety of the biosimilar used in naïve patients as well as in situations of a single switch (original to biosimilar or vice versa).
In fact, what is not clear so far is the ideal time for this switch. Considering switch from biologicals innovator to biosimilar, GEDIIB acknowledges the following:
We should not switch if clinical response was not achieved with the initial biological therapy.
Before switching, patient must be stable on clinical remission based on clinical, laboratorial and endoscopic data.
There should be no suspicion or report of any immunogenicity reaction with the initial biological therapy before switching.
ECCO (European Crohn’s and Colitis Organization): In 2017, ECCO have published a positioning statement regarding biosimilars. All other European IBD societies follow the same ideas of ECCO [25]:
Once a biosimilar is registered in the European Unit by the EMA (European Medical Agency), this product should be considered efficacious and safe to be used.
ECCO acknowledges that biosimilarity is better characterized by performing suitable
ECCO also acknowledges transitioning from the originator to a biosimilar in IBD patients. Observational switching studies can provide valuable evidence concerning safety and efficacy. Scientific and clinical evidence is still lacking regarding reverse switching, multiple switching and cross-switching among biosimilars in IBD patients.
It is consensus between the main societies that switching from originator to a biosimilar should be performed following appropriate discussion between physicians, nurses, pharmacists and patients, and according to national recommendation. The IBD nurse can play a key role in communicating the importance and equivalence of biosimilar therapy.
CCFA (Crohn’s and Colitis Foundation of America) is a professional organization for those physicians, nurses, scientists and other health providers who care for IBD patients in United States. CCFA support all decision of the Food and Drug Administration (FDA) regarding biosimilar approval and its role in ensuring safety of patients. CCFA also acknowledges that all biologicals, innovator or biosimilar should undergo through human testing and meet the highest safety standards. Considering interchangeability, CCFA urges the FDA to provide reasonable proof that switching from originator to the biosimilar would not incur in immunogenicity or loss of response to the innovator, and vice versa.
In summary, IBD societies (ECCO, GEDIIB and CCFA) support a single transition between biologicals, as long as the patients are on clinical remission. Moreover, CCFA believes that when any transition occurs, both patient and physician must be informed of the exact drug the patient is receiving. In agreement with other societies, CCFA does not support multiple switches due to lack of clinical and scientific evidence [26].
Nowadays, what is really being discussed at the medical literature is interchangeability between biological products. The American FDA defined that interchangeability is when the product is expected to produce the same clinical result as the reference product in any given patient. Also, for products administered to a patient more than once, the risk in terms of safety and reduced efficacy of switching back and forth between a candidate interchangeable biologic and its reference product should be evaluated by a clinical study specifically designed for these endpoints [27, 28]. Once approved by FDA’s high standards, an interchangeable biologic may be substituted by biosimilar or vice versa, without any involvement of the prescriber [27, 28].
On the other hand, EMA has reported a totally different definition regarding interchangeability of biologics. For the European group, FDA’s perception of interchangeability is based in the American legislation and corresponds to an automatic substitution by the European agency terminology. Biosimilars are copy versions of an already existing biological product and approved by a regulatory agency. Then, it is expected to be a high-quality product, efficacious and safe. Because of the high similarity to the innovator, EMA believes that there is no reason for the immune system of the treating patients to respond differently than when the same patient was exposed to the innovator product. That is why EMA advocates that interchangeability is not a legal but a scientific and medical term. Once approved as a biosimilar, it can be interchangeable. EMA regulators stated that they have no intention to create a new legal regulatory requirement for interchangeability of biologics. Indeed, European regulators believe that this dichotomy would create two classes of biosimilars: the interchangeable (approved after being evaluated in a clinical trial specifically designed as required by FDA) and those not interchangeable [28, 29].
In Brazil, so far, health authorities did not issue any specific regulation regarding interchangeability of biological products. A technical note published by ANVISA in October 2018 concluded that interchangeability and substitution are more directly related to clinical practice than to regulatory status. Moreover, ANVISA believes that interchangeability and substitution involve broader aspects, such as specific studies conducted by companies, data from the literature, medical evaluation in each case and cost-effectiveness. Moreover, the Brazilian agency also reported the importance of a medical evaluation and adequate pharmaceutical care in the case of switching from an innovator to a biosimilar. ANVISA also believes that multiple exchanges between biosimilar products and the comparator biological product are not suitable, and traceability and monitoring of use are very difficult in these cases. In fact, ANVISA gave to both, the prescriber physician and the Brazilian Ministry of Health, power to decide about switching between biological products [30]. However, without any recommendation and regulation, unusual scenarios of multiple switches may occur and the appropriate pharmacovigilance will be impaired, compromising the safety of the treatment.
Since the approval of the first monoclonal antibody biosimilar, CT-P13, by the EMA, several observational studies reported the effectiveness and safety of a single switch between a biologic reference and a biosimilar in the IBD’s treatment scenario [31]. Others have reported a significant cost savings with the treatment after incorporating biosimilar in the medical practice. On the basis of these findings, it would be likely that switching to biosimilars would no longer be an option but the routine approach for patients who are candidates for biological drugs [32, 33]. However, it has been observed at the literature some problems regarding switching from originator to biosimilars. Chaparro and colleagues in Spain reported a series with almost 200 IBD patients who switch from infliximab reference to CT-P13 and compared the results to patients kept on the originator. Authors observed higher rates of relapse on the switching group. The cumulative incidence of relapse was 2% at 6 months and 10% at 24 months. In the multivariate analysis, the switch to CT-P13 was associated with a higher risk of relapse (HR = 3.5, 95% confidence interval [CI] = 2–6) [34]. A recent systematic review and metanalysis by Queiroz et al. reported that discontinuation rates following a switch to a biosimilar in patients with IBD increase over time [20]. Moreover, not long ago, a study by IQVIA analyzed a very large database of German patients with immuno-mediated diseases treated with biologics, which includes ~60% of all prescriptions reimbursed by statutory health insurance funds in Germany [35]. Approximately 30% of patients switched back from an etanercept/infliximab biosimilar to an etanercept/infliximab reference product within 12 months after the initial biosimilar therapy. The authors found no significant effect of different factors, such as age, gender, physician specialty and concomitant therapy [35]. It was speculated by the academic community that discontinuation of the treatment may occur due to a nocebo effect.
Recent studies have assessed the safety and effectiveness of switching to other infliximab biosimilars that became available after CT-P13 and to adalimumab biosimilar. A prospective and observational Germany cohort study described the 80-week follow-up of 144 patients with inflammatory bowel disease after switching from infliximab to a biosimilar (SB2). The same recommendations for the use of infliximab were maintained for the new drug. All patients received infliximab induction and the time to switch to the biosimilar was variable (the mean duration of previous infliximab therapy was 30 months). Most patients were in remission at the time of switch, 36% had mild to moderate clinical activity and none had severe activity. Despite the limitations of the study, it was observed that the disease activity was not affected by the transition to biosimilar, the switching was not associated with lack of effectiveness and was well tolerated [36].
An observational cohort study included 481 patients treated with SB5 (Sb5-switch cohort and SB5-start cohort) over 12 months of follow-up. The biosimilar was effective and safe. The observed rates of primary non-response and secondary loss of response in the switched cohort were similar to those previously reported to the originator [37].
Reverse, multiple and cross-switches will be a challenge for the next years to come. It has been incorporated in clinical practice the need to switch from an originator to a biosimilar. Moreover, some new demanding situations already have come to the biosimilar era. We clinicians now face not only a single switch but also the switch in the opposite direction, for instance, when relapse or adverse effect are observed after a switch between biologics. Furthermore, we will face, in the next months or years, multiple switches among different molecules from one biosimilar to another—named cross-switch. However, we do not have strong evidence to support this new kind of switches. Few observational studies have been reported so far. Ilias and co-authors analyzed 174 patients with Crohn and ulcerative colitis in maintenance therapy with CT-P13 who switched back to reference infliximab due to reimbursement policies in Hungary. No significant changes were observed in remission, trough levels or antidrug antibodies in patients switched from the biosimilar to remicade. No new safety signals were detected [38].
For the very first time, an Italian group has reported multiple switches in IBD. The Sicilian Network for Inflammatory Bowel Disease group analyzed almost 230 patients: 127 (46.0%) were naïve to IFX and naïve to anti-TNFs, 65 (23.5%) were naïve to infliximab and previously exposed to anti-TNFs, 17 (6.2%) were switched from an infliximab reference to a biosimilar (SB2), 43 (15.6%) were switched from the biosimilar CT-P13 to SB2 and 24 (8.7%) were multiply switched (from infliximab reference to CT-P13 and to SB2) [39]. They observed 67 serious adverse in 57 patients (20.7%; incidence rate: 36.7 per 100 patient-year) and 31 of these events lead to withdrawal. The effectiveness after 8 weeks of treatment was evaluated in patients naïve to IFX (
A prospective multicenter cohort study evaluated the effectiveness and safety of multiple switches in inflammatory bowel disease. One hundred and seventy-six patients were included and divided into three groups (Originator to CT-P13, CT-P13 to SB2 and Originator to CT-P13). Patients had variable previous duration of IFX exposure before index switch (minimum median of 1.9 years), mostly in clinical remission. The dose and interval were maintained after the switch and were only modified if clinically necessary. Similar rates of clinical and biochemical remission were observed in the three groups at 12 months after the most recent switch. Increased immunogenicity was not observed after multiple successive switches [41].
A Dutch multicenter retrospective study assessed the need for reverse switch to infliximab among patients with inflammatory bowel disease using biosimilars (CT-P13). Among 758 patients who switched to CT-P13 after median of 4.7 years of treatment with originator, reverse switching was observed in almost 10% of patients mainly due to gastrointestinal and dermatological symptoms. In nine patients, the reason for switching was loss of response. No relevant differences in pharmacokinetics or immunogenicity were observed. Reverse switching was beneficial in 73.3% of patients and may be considered in case of loss of response or adverse effects following an initial switch [42].
As the reader may see, we just have few reports regarding multiple switches and cross-switch reported in the literature. Further experience in different scenarios will certainly fill in the knowledge gaps and pave the way to increase clinicians’ confidence in their clinical practice.
Almost one decade after the first approval of a monoclonal antibody biosimilar by the EMA in 2013 [43], an underestimated phenomenon has been observed in patients treated with biological drugs: the nocebo effect [44, 45, 46, 47].
Biological treatment is currently part of the medical practice in inflammatory bowel disease management. However, as already discussed in this chapter, the higher cost of the treatment of immune-mediated diseases is directly related to the cost of biological drugs. In this scenario, biosimilar drugs were created. No long ago, higher-than expected discontinuation of treatment rates possible related to nocebo effect has been observed in patients who switched from a stable treatment with the originator infliximab to the biosimilar CT-P13 [20].
Nocebo effect is a physiological, psychological and neurobiological phenomenon related to a perceived harm that occurs as a consequence of patients’ negative expectancies not associated with known pharmacologic actions of the treatment. More recently, after the beginning of the biosimilar era, the concept of nocebo was revisited and defined as the negative equivalent of the placebo effect. Since then, this concept has received considerable attention in both clinical research and clinical practice [44, 45, 46]. Even though medical evidence supports biosimilar use, several barriers were created to hinder more widespread adoption of these drugs into current medical practice. Slow uptake of biosimilars in clinical practice may reflect gaps in patients’ and clinicians’ knowledge and understanding of these drugs risks and benefits. For sure, this fact has stimulated interest in the potential role of nocebo phenomenon [20, 47, 48].
It has been proposed that different neurobiological pathways may play a role in the effect of negative expectations on patients’ perceptions. In fact, the majority of the studies came from the field of pain perception, a method to better understand nocebo effect. Some pathways were supposed to be involved: activation of the hypothalamic-pituitary-adrenal axis and CCKergic systems (CCK = cholecystokinin), as well as decreasing dopamine and opioid activity may play a role in the pathophysiology of nocebo effect. The neuroanatomical regions contributing to the nocebo effect are most likely different than those contributing to the placebo effect [48].
Odinet and colleagues analyzed the nocebo effect in a systematic review. Authors concluded that there are insufficient data published to confirm a biosimilar nocebo effect, although higher discontinuation rates in infliximab biosimilar open-label studies support this theory. They also outlined many limitations in this systematic review to draw strong conclusions. Further studies are needed to evaluate the existence of a biosimilar nocebo effect. If it does indeed exist, the effects of mitigation strategies such as prescriber education and patient empowerment should be evaluated [47].
The nocebo effect, at least in part, may be responsible for higher rates of discontinuation of treatment after switching from an innovator biological to a biosimilar. In the aforementioned systematic review and metanalysis by Queiroz et al., our group reported that discontinuation rates following a switch to a biosimilar in patients with IBD increase over time. However, it was not possible to confirm the nocebo effect as the unique reason for discontinuation [20].
In the earliest years of marketing of biosimilars, the perspective of IBD specialists regarding biosimilars was very conservative [49]. Previous survey-based studies with gastroenterologists have shown a significant unawareness of biosimilar medications in general [50, 51]. On the other hand, it has been previous demonstrated that educational initiatives can increase confidence regarding biosimilar use in clinical practice [52]. Little is known about the comprehension and perception of Brazilian gastroenterologists about biosimilars. In 2016, the Brazilian Study Group of Inflammatory Bowel Diseases (GEDIIB) conducted an anonymous web-based survey with IBD-expert gastroenterologists regarding their current knowledge of biosimilar monoclonal antibodies. The volunteers responded to 22 multiple-choice questions contemplating issues such as their confidence and concerns of using biosimilars, their opinion about non-medical switching and their need of educational activities. To evaluate changes in perception of specialists, a similar follow-up questionnaire with 14 multiple-choice questions was later developed by the GEDIIB. It was delivered during the II Brazilian Congress of Inflammatory Bowel Diseases audience, between March 29 and 31, 2019. Both surveys were non-interventional and offered self-selective recruitment. A simple descriptive comparison of data between the two questionnaires was carried out.
A total of 61 respondents replied to the survey. Most worked in private clinics (72%) and in public hospitals (49%), and 70% occupied high positions, such as professors, head of Gastroenterology departments and head of IBD units. The majority of them lived in the southeastern region, where the most developed IBD referral centers are located in Brazil. In total, 95% answered that they were responsible for biologic therapy prescription and two-thirds of them had more than 5 years of experience in prescribing biologics.
The similar questionnaire was applied to 731 gastroenterology physicians. Most of the volunteers responded that they lived in the southeastern region, 41% worked in public hospitals, while 39% worked in private clinics. The majority of the physicians (67%) declared to have access to biosimilars; however, 40% had never prescribed the medication.
The majority of participants considered that biosimilars are less expensive (77% in 2016; 86% in 2019) than the originator. In both surveys, about half of the responders thought that biosimilars have equivalent efficacy, and about 14% thought that biosimilars will have more indications than the originator. In 2019, a much lower percentage of participants considered that the immunogenicity of biosimilars is the same than the originator (21% compared to 47% in 2016). Figure 2 summarizes the answers to general concepts of biosimilars.
General concepts of biosimilars in 2016 and 2019.
The majority of responders disagreed with substitution of the originator with a biosimilar by a pharmacist (82% in 2016; 92% in 2019), although, in 2019, 8% agreed with automatic substitution only for new prescriptions. When asked if they would switch a patient in remission from the originator to a biosimilar, most (92% in 2019) responded they would not make a switch, even in patients with sustained remission. Figure 3 illustrates the responses regarding substitution and switch.
Responses regarding substitution and switch in 2016 and 2019.
Expert gastroenterologists still show concerns regarding the efficacy and safety when prescribing biosimilars. The percentage of totally confident and very confident to prescribe these medications decreased from 23% in 2016 to only 4% in 2019, while 56% of respondents were little confident and 21% have no confidence in prescribing this medication in 2019—worse compared to 2016. Figure 4 summarizes confidence in biosimilars.
Confidence in biosimilars in 2016 and 2019.
In the 2019 survey, 59% of participants reported that education in biosimilars is confusing and the majority agreed that educational activities involving biosimilars are needed (94%), as well as greater collaboration between societies to develop guidelines in biosimilars (95%) and the development of records for monitoring the safety of biosimilars (99%).
In a recent similar survey, European IBD phisicians were asked about the use of biosimilars in 2013 and 2015. Unlike our research, their study demonstrated that a better understanding of the process of developing biosimilars and their regulatory process contributed to a change in the perception of IBD experts about biosimilars and, consequently, they became more confident in prescribing biosimilars [52]. Conversely, in our study, there was a worsening in the confidence of IBD physicians in prescribing biosimilars over time. This difference between the European and Brazilian surveys may reflect the lack of knowledge of Brazilian physicians about biosimilars and shed light for the development of appropriate educational strategies in Brazil.
As the patents of biologics are expiring, biosimilars represent a promising opportunity to expand access to biological therapies due to price competition and cost savings. Although this chapter provides a comprehensive overview of the current state of knowledge on biosimilars in IBD, knowledge gaps remain, especially concerning different strategies of switching (e.g., cross-, multiple-). The widespread adoption of biosimilars will enable increasing knowledge and experience with biosimilars, which will pave the way toward an improved acceptance and decreased negative expectations with the incorporation of these drugs in clinical practice.
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When deciding the most effective non-pharmacological technique, take into consideration the patient’s age, developmental level, medical history and prior experiences, current degree of pain and/or anticipated pain. The advantage of non-pharmacological treatments is that they are relatively inexpensive and safe.",book:{id:"7289",slug:"pain-management-in-special-circumstances",title:"Pain Management in Special Circumstances",fullTitle:"Pain Management in Special Circumstances"},signatures:"Ahmed El Geziry, Yasser Toble, Fathi Al Kadhi, Muhammad Pervaiz\nand Mohammad Al Nobani",authors:null},{id:"63463",title:"Clinical Classification of Cerebral Palsy",slug:"clinical-classification-of-cerebral-palsy",totalDownloads:2575,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"The classification of cerebral palsy (CP) remains a challenge; hence the presence of so many classifications and a lack of consensus. Each classification used alone is incomplete. 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The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. 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