*2.5. FEM-DEM*

FEM-DEM is a hybrid approach that combines the advantages of DEM with finite element modelling (FEM) to reduce the computational load. The DEM component is applied within model micro-scale sections, and the stresses resultant from the DEM are then imposed within the FEM, which models the macro-scale domain [38]. This method is most applicable if the domain can be discretised into high- and low-sensitivity subdomains. It should also be mentioned that FEM-DEM codes are available that combine these two methods for different purposes [27,28].

#### *2.6. Equivalent Continuum Methods (ECM)*

Equivalent continuum methods assume that within a representative element volume (REV) the medium can be treated as homogeneous. Instead of defining fractures individually and modelling the strength degradation, this means that the properties of the domain are generalised and modelled as a continuum. The region of interest can then be discretised based on the regions of high and low fracture density, allowing for the modelling of the fractured and virgin zones of the reservoir [18,39]. The use of an ECM representation makes it simpler to apply well established numerical approaches such as the finite element method (FEM) to solve governing equations that describe the physical processes and behaviour of the medium.

Most of previous applications of ECM are focused on soils and near-surface materials [29–32], rather than for modelling hydraulic fracturing in rocks at a greater depth. This may be due to the general availability of a wide range of empirical methods to define the properties of fractured materials at shallow depths [40,41].

A novel ECM method introduced in this paper attempts to address the necessity of optimised hydraulic fracturing modelling. The introduced method in this paper uses the dependency of the permeability on void ratio to define the hydraulic fracture propagation. This method allows for an easier convergence due to uniform mesh dimensions and the exploitation of an already present coupled fluid flow and continuum relations.


**6. Recent clinical trials and experience**

than treatment with a purified cannabinoid [42, 44]. This is supported by preclinical studies. In the *in vitro* oxotremorine-M mouse model of epilepsy, excessive neuronal bursting activity

Ca2+ in rat hippocampal neuronal and glial cells. This effect is compounded when the two compounds are mixed together, with the greatest effect occurring with whole plant extract

'entourage' effects between the various cannabinoids provide therapeutic benefit of cannabis whole plant extract, benefit that exceeds the activity of a single purified cannabinoid. This

The use of cannabis as a treatment for a variety of ailments in eastern and Mediterranean cultures over the last several millennium has been well documented [47]. The first description of the use of cannabis to treat seizures came from Dr. W. O'Shaugnessy who while working in India reported its successful use to treat seizures in an infant [48]. Following this, cannabis extracts became widely used throughout Europe and North America as an accepted treatment for epilepsy [49]. Following prohibition and with the introduction of other anticonvulsants,

During the mid-twentieth century, several reports on the effect of recreational cannabis consumption surfaced with contrasting effects. Several case reports described patients having decreased seizure frequency following the consumption of cannabis [50]. Cannabis consumption was also shown to be protective against first unprovoked seizures. In adult males who smoked cannabis in the last 90 days, the odds of having a first unprovoked seizure was 0.38 compared to adult males who never consumed cannabis [51]. Conversely, a patient with a history of epilepsy who had been seizure free for several months on medication was reported

In 1978, Mechoulam et al. reported their double blinded placebo-controlled study of CBD used as an add-on therapy in patients with refractory focal onset seizures. Of the four patients who took CBD two were seizure free for the 3 months of the study while another had partial improvement. None of the five patients who took placebo had any improvement in their seizures [53]. Cunha et al. reported the results of their study investigating the potential of CBD in patients with refractory temporal lobe epilepsy. In the first phase of the study, healthy adult volunteers were randomized to receive either placebo or CBD at 3 mg/kg/day for 30 days. Of 8 volunteers receiving CBD, 2 reported somnolence otherwise no adverse effects were reported. In the second phase, 15 adult patients with drug-resistant temporal lobe epilepsy were randomized to receive either placebo or CBD (up to 300 mg/day) for a period of 18 weeks in a double-blinded manner. Four of 8 patients dosed with CBD had complete improvement while three had partial improvement. No adverse effects were noted in patients given CBD [54].

to have had an exacerbation of seizures following the consumption of cannabis [52].

**5. Early clinical experience with cannabis for the treatment of**

cannabis fell out of use as a treatment for epilepsy in western cultures.

can be suppressed with ∆9

208 Recent Advances in Cannabinoid Research

remains to be demonstrated in the human clinical context.

ing both ∆9

**epilepsy**

containing both ∆9

∆9

In recent years there has been a public perception that cannabis is a potent, natural, and safe alternative therapy for epilepsy. This has driven the demand for and use of cannabis and its derived products to treat epilepsy especially in those patients whose seizures are medically intractable. Coupled with the media exposure showing examples of the apparent miraculous effects of CBD oil in select epileptic patients, treating physicians have struggled to balance the patient demand for cannabis products and the need for studies to determine their, efficacy, dosing, side-effect profile, and indication. To that end, there have been multiple studies, predominantly in children, looking into these clinical questions. Unfortunately, the overwhelming majority of these studies have been retrospective, unblinded, and uncontrolled resulting in their being hampered by various forms of bias and potential placebo effect. Despite the plethora of published research on this topic, questions still remain on the use of cannabis in epilepsy.

In this section, we will review the limitations of the studies, the studies using artisanal and CBD enriched cannabis herbal extracts (CHE), the studies using highly purified pharmaceutical grade CBD, and a meta-analysis of the CBD studies.

#### **6.1. Limitations of the studies**

The widespread use of cannabis and the effect of bias are highlighted in various published surveys. McLachlan performed a survey in London, Ontario, Canada, in which more than 60% of patients declared that cannabis was effective for their seizures and stress levels [56]. Ladina et al. reported a case series of 18 patients who all found medicinal cannabis very helpful for seizure control and improvement of mood disorder [57]. By contrast, Press had reported a significant discrepancy in reported responder rate between preexisting Colorado residents and those who moved to Colorado to obtain cannabis to treat their child's epilepsy (22 vs. 47%) suggesting there is a significant perception bias among these children's caregivers as to the therapeutic benefits of cannabis [58]. Physician bias may also play a role as a recent survey by Mathern showed contrasting opinions about CBD between neurologists and the general public. In his study, a minority of epileptologists and general neurologists said that there were sufficient data safety (34%) and efficacy data (28%) and only 48% would advise using medical cannabis and only in severe cases of epilepsy. Conversely, nearly all patients and the general public responded that there was sufficient safety (96%) and efficacy (95%) data, and 98% would recommend cannabis in cases with severe epilepsy [59].

Given the present approved indications for medical coverage, the high cost of pharmaceutical grade CBD products, and the illegal status of cannabis in some countries and US states, the overwhelming majority of patients will at this time be using CBD oil extracts or artisanal products. In many jurisdictions these products are unregulated and therefore their content and consistency are uncertain and can vary. In Australia, where medical use of cannabis is highly restricted, Suraev reported that in parents treating their children with "illicit" cannabis extracts, the majority of extract samples used by the families contained low concentrations of cannabidiol, while Δ9 -THC was present in nearly every sample [60]. These findings highlighted the profound variation in the illicit cannabis extracts being used. Studies examining the use of artisanal and CBD oil extracts therefore could have had uncertain and inconsistent amounts of cannabinoids. This inconsistency in combination the inherent problems of retrospective studies, make the findings of these studies questionable; moreover, none of published studies included serum CBD levels.

in quality of life measures and spike index on electroencephalogram (EEG). Adverse events

The Cannabinoid Research Initiative of Saskatchewan is currently conducting a Canadian, multicenter, prospective, open-label, dose-escalation phase 1 trial entitled Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E). The source of the CBD oil is consistent

of the cannabinoids in the CHE were confirmed through Health Canada Quality Assurance and Good Manufacturing Practices (GMP) certification [64]. Preliminary data showed that all 6 participants had improvements in seizure frequency, Quality of Life in Childhood Epilepsy (QOLCE) and EEG rating scores—with three participants showing continued improvements in these measures after the oil extract was discontinued. In addition, serum CBD levels suggested linear dose independent pharmacokinetics in all but one participant. In most participants, serum

intoxication clinically throughout the study. Preliminary data suggests that an effective and welltolerated CBD initial target dose of 5–6 mg/kg/day is effective and well tolerated when a 1:20 Δ9

THC:CBD CHE is used. In addition, the serum concentration of CBD follows dose-independent linear pharmacokinetics for most participants, although non-linear pharmacokinetics might occur but requires confirmation. Continued improvement in seizure frequency and QOLCE following the discontinuation of CHE suggest a possible enduring anticonvulsant effect [65].

With the production of a highly purified, pharmaceutical grade CBD (Epidiolex), studies could now be performed with a CBD source of greater reliability. Although potential bias

Devinksy published an open label trial in patients aged 1–30 with severe, intractable, childhood-onset, drugs resistant epilepsy. All patients were receiving their regular anti-epileptic drugs. Patients were given CBD at 2–5 mg/kg/day, titrated over a period of 2 weeks till intolerance or to a maximum dose of 25 mg/kg to 50 mg/kg/day. The main objective of the study was to establish safety and tolerability of CBD and the primary end point was the median percentage in the mean monthly frequency of motor seizures at 12 weeks. This study included mainly patients with Dravet and Lennox-Gastaut syndromes. One hundred and sixty-two patients were enrolled. A significant high rate of adverse events was reported in 128 patients (79%). The most common were somnolence (n = 41 [25%]), decreased appetite (n = 31 [19%]), diarrhea (n = 31 [19%]) and fatigue (n = 21 [13%]). This high rate of side effects (many of which were seen during the titration period) suggests that too rapid a titration rate may predispose toward side effects. The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) at 12 weeks of treatment. The median reduction in

From this same cohort, Rosenberg et al. reported that caregivers of 48 patients indicated an 8.2–9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness,

at the maximum dose of oil extract. None of the participants displayed any evidence of Δ9

**6.3. The highly purified, pharmaceutical grade CBD products**

remained, better clinical studies had been performed.

monthly motor seizures was 36·5% (IQR 0–64·7) [66].

Cannabis for Pediatric and Adult Epilepsy http://dx.doi.org/10.5772/intechopen.85719

211

during the titration period included somnolence, anorexia and diarrhea [63].

with a single batch of 1:20 Δ9

Δ9

To date, there are few prospective, double blind, placebo-controlled studies which all only examined the use of the highly purified, pharmaceutical grade CBD (Epidiolex). None involved artisanal CBD or the CBD oil extracts.

#### **6.2. The artisanal and CBD oil extracts**

While keeping the limitations of the studies examining artisanal and CBD oil extracts in epilepsy in mind, most of these studies did find that CBD oil extracts are effective in reducing seizures and improving quality of life.

Tzadok reported out of 74 children being treated with a 20% CBD and 1% Δ9 -THC CHE, 89% reported reduction in seizure frequency with only 43% of patients having a >50% reduction in seizures. Five patients reported aggravation of seizures leading to withdrawal from the study. Improvement in behavior and alertness, language, communication, motor skills and sleep were noted. Adverse reactions included somnolence, fatigue, gastrointestinal disturbances and irritability leading to withdrawal of cannabis use in five patients. The CBD dosing ranged from 1 to 20 mg/kg/day with 83% taking <10 mg/kg/day [61].

Similarly, Porcari retrospectively studied the efficacy of artisanal CBD preparations in children with epilepsy. The study also included a subgroup comparison to determine if the addition of clobazam was related to any beneficial effects of CBD. Overall, the addition of CBD resulted in 39% of patients having a >50% reduction in seizures, with 10% becoming seizure-free. The difference in effect between CBD alone and CBD with clobazam was not statistically significant. Increased alertness and improved verbal interactions were reported in 14% of patients in the CBD group and 8% of patients in the CBD and clobazam group. The average dose of CBD was 2.9 mg/kg/day in the CBD group and 5.8 mg/kg/day in the CBD and clobazam group [62].

McCoy et al. performed a prospective open label study using a 2:100 Δ9 -THC:CBD CHE in 20 children with Dravet syndrome. The dose of CBD ranged from 7 to 16 mg/kg/day (mean 13.3 mg CBD/kg/day). They reported that during the 20-week intervention period the median monthly reduction in motor seizures was 70.6%. The CHE also resulted in improvements in quality of life measures and spike index on electroencephalogram (EEG). Adverse events during the titration period included somnolence, anorexia and diarrhea [63].

The Cannabinoid Research Initiative of Saskatchewan is currently conducting a Canadian, multicenter, prospective, open-label, dose-escalation phase 1 trial entitled Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E). The source of the CBD oil is consistent with a single batch of 1:20 Δ9 -THC:CBD CHE used for all study participants. Concentrations of the cannabinoids in the CHE were confirmed through Health Canada Quality Assurance and Good Manufacturing Practices (GMP) certification [64]. Preliminary data showed that all 6 participants had improvements in seizure frequency, Quality of Life in Childhood Epilepsy (QOLCE) and EEG rating scores—with three participants showing continued improvements in these measures after the oil extract was discontinued. In addition, serum CBD levels suggested linear dose independent pharmacokinetics in all but one participant. In most participants, serum Δ9 -THC concentrations remained lower than what would be expected to cause intoxication even at the maximum dose of oil extract. None of the participants displayed any evidence of Δ9 -THC intoxication clinically throughout the study. Preliminary data suggests that an effective and welltolerated CBD initial target dose of 5–6 mg/kg/day is effective and well tolerated when a 1:20 Δ9 - THC:CBD CHE is used. In addition, the serum concentration of CBD follows dose-independent linear pharmacokinetics for most participants, although non-linear pharmacokinetics might occur but requires confirmation. Continued improvement in seizure frequency and QOLCE following the discontinuation of CHE suggest a possible enduring anticonvulsant effect [65].

#### **6.3. The highly purified, pharmaceutical grade CBD products**

Given the present approved indications for medical coverage, the high cost of pharmaceutical grade CBD products, and the illegal status of cannabis in some countries and US states, the overwhelming majority of patients will at this time be using CBD oil extracts or artisanal products. In many jurisdictions these products are unregulated and therefore their content and consistency are uncertain and can vary. In Australia, where medical use of cannabis is highly restricted, Suraev reported that in parents treating their children with "illicit" cannabis extracts, the majority of extract samples used by the families contained low concentrations

lighted the profound variation in the illicit cannabis extracts being used. Studies examining the use of artisanal and CBD oil extracts therefore could have had uncertain and inconsistent amounts of cannabinoids. This inconsistency in combination the inherent problems of retrospective studies, make the findings of these studies questionable; moreover, none of pub-

To date, there are few prospective, double blind, placebo-controlled studies which all only examined the use of the highly purified, pharmaceutical grade CBD (Epidiolex). None

While keeping the limitations of the studies examining artisanal and CBD oil extracts in epilepsy in mind, most of these studies did find that CBD oil extracts are effective in reducing

reported reduction in seizure frequency with only 43% of patients having a >50% reduction in seizures. Five patients reported aggravation of seizures leading to withdrawal from the study. Improvement in behavior and alertness, language, communication, motor skills and sleep were noted. Adverse reactions included somnolence, fatigue, gastrointestinal disturbances and irritability leading to withdrawal of cannabis use in five patients. The CBD dosing ranged

Similarly, Porcari retrospectively studied the efficacy of artisanal CBD preparations in children with epilepsy. The study also included a subgroup comparison to determine if the addition of clobazam was related to any beneficial effects of CBD. Overall, the addition of CBD resulted in 39% of patients having a >50% reduction in seizures, with 10% becoming seizure-free. The difference in effect between CBD alone and CBD with clobazam was not statistically significant. Increased alertness and improved verbal interactions were reported in 14% of patients in the CBD group and 8% of patients in the CBD and clobazam group. The average dose of CBD was 2.9 mg/kg/day in the CBD group and 5.8 mg/kg/day in the CBD and

20 children with Dravet syndrome. The dose of CBD ranged from 7 to 16 mg/kg/day (mean 13.3 mg CBD/kg/day). They reported that during the 20-week intervention period the median monthly reduction in motor seizures was 70.6%. The CHE also resulted in improvements

Tzadok reported out of 74 children being treated with a 20% CBD and 1% Δ9

McCoy et al. performed a prospective open label study using a 2:100 Δ9

from 1 to 20 mg/kg/day with 83% taking <10 mg/kg/day [61].

of cannabidiol, while Δ9

210 Recent Advances in Cannabinoid Research

lished studies included serum CBD levels.

**6.2. The artisanal and CBD oil extracts**

seizures and improving quality of life.

clobazam group [62].

involved artisanal CBD or the CBD oil extracts.

With the production of a highly purified, pharmaceutical grade CBD (Epidiolex), studies could now be performed with a CBD source of greater reliability. Although potential bias remained, better clinical studies had been performed.

Devinksy published an open label trial in patients aged 1–30 with severe, intractable, childhood-onset, drugs resistant epilepsy. All patients were receiving their regular anti-epileptic drugs. Patients were given CBD at 2–5 mg/kg/day, titrated over a period of 2 weeks till intolerance or to a maximum dose of 25 mg/kg to 50 mg/kg/day. The main objective of the study was to establish safety and tolerability of CBD and the primary end point was the median percentage in the mean monthly frequency of motor seizures at 12 weeks. This study included mainly patients with Dravet and Lennox-Gastaut syndromes. One hundred and sixty-two patients were enrolled. A significant high rate of adverse events was reported in 128 patients (79%). The most common were somnolence (n = 41 [25%]), decreased appetite (n = 31 [19%]), diarrhea (n = 31 [19%]) and fatigue (n = 21 [13%]). This high rate of side effects (many of which were seen during the titration period) suggests that too rapid a titration rate may predispose toward side effects. The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) at 12 weeks of treatment. The median reduction in monthly motor seizures was 36·5% (IQR 0–64·7) [66].

From this same cohort, Rosenberg et al. reported that caregivers of 48 patients indicated an 8.2–9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global quality of life (QOL). Interestingly, these differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure reducing effects [67].

12 months, −57% at 15 months and −55% at 18 months. The transdermal patch was well tolerated. Serious adverse events were as follows: seizures (n = 2) and increased anxiety (n = 1); one death was reported after the 15 month visit. In addition, no significant elevations in alanine aminotransferase and aspartate aminotransferase levels >3 times upper limit of normal were

In comparing cannabis derived treatments to standard therapies, it is worthwhile to note that the STICLO group examining the effects of stiripentol in Dravet patients in a double blind randomized placebo controlled study showed that 15 (71%) patients had >50% seizure reduction (including nine free of clonic or tonic-clonic seizures) compared to only one (5%) on placebo (none were seizure free; stiripentol 95% CI 52.1–90.7 vs. placebo 0–14.6). Stiripentol's responder rate is therefore suggested to be superior to Epidiolex with a far lower placebo responder rate [72]. Similarly, in a double-blind, randomized, placebo-controlled trial of the anti-epileptic drug rufinamide in patients with Lennox-Gastaut syndrome, the median percentage reduction in total seizure frequency was greater in the rufinamide therapy group than in the placebo group (32.7 vs. 11.7%, p = 0.0015). There was also a difference (p < 0.0001) in tonic-atonic ("drop attack") seizure frequency with rufinamide (42.5% median percentage reduction) vs. placebo (1.4% increase). These findings are comparable with the results with Epidiolex. One also has to keep in mind that the median reduction of atonic seizures in the placebo group was markedly higher with the Epidiolex study suggesting potential bias [73]. Of note, the results from the study by McCoy et al. and the preliminary data from CARE-E study showed a much higher responder rate than those with pharmaceutical grade CBD. This appar-

effect in which the various cannabinoids can act synergistically with one another [42, 44].

The cannabinoids found in cannabis appear to offer a unique pharmacological mode of action in the treatment of epilepsy. This, combined with the apparent low risk of serious side effects, makes cannabis and an attractive potential option for patients with treatment resistant epilepsy. Currently, there is a large public perception that cannabis products are superior to and safer than conventional anti-epileptic medications especially in treating patients with Dravet syndrome and other pediatric onset epileptic encephalopathies. Based on interpretation of the available data, the authors feel that cannabis based therapies show promise in the treatment of children with treatment resistant epilepsies. While the studies to date assessing cannabis based therapies for the treatment of epilepsy have been encouraging, they should be interpreted with caution. At this time, the long-term adverse effects, the indicated epilepsy and seizure types suitable for treatment with cannabis, the dosing of CBD and other cannabinoids, remain unknown. Also, there is minimal data regarding the pharmacokinetics of the cannabinoids especially in children and when used in patients with multiple concomitant medications. Moreover, the existing studies are limited with the majority of them being retrospective

and subject to bias, possible placebo effect, and other limitations.

Cannabis for Pediatric and Adult Epilepsy http://dx.doi.org/10.5772/intechopen.85719 213

seen [71].

ent superiority of a CHE containing Δ9

**7. Conclusion**

Devinsky et al. later performed a double blind, placebo-controlled trial in patients with Dravet syndrome including 120 children and young adults using Epidiolex with a CBD dosage of 20 mg/kg/day. The median frequency of convulsive seizures per month decreased from 12.4 (baseline) to 5.9 with CBD, as compared with a decrease from 14.9 (baseline) to 14.1 with placebo (adjusted median difference between cannabidiol vs. placebo was −22.8% points [CI], −41.1 to −5.4; p = 0.01). The percentage of patients who had at least a 50% reduction in convulsive seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93–4.30; p = 0.08). This study shows an overall benefit of CBD over placebo but also a large placebo effect in the control group [68].

Another trial that assessed the efficacy of Epidiolex in reducing atonic seizures in patients with Lennox-Gastaut syndrome. In this double blind, placebo-controlled trial, a total of 225 patients were enrolled, 76 patients were assigned to a treatment group (20 mg/kg/day CBD) and 76 to the placebo group. The median percent reduction from baseline in monthly atonic seizure frequency during the treatment period was 41.9% in the treatment group vs. 21.8% in the placebo group. As with the other studies assessing Epidiolex, the most common adverse events among the patients in the treatment groups were somnolence, decreased appetite, and diarrhea [69].

A recent systematic review assessed the safety and efficacy of pharmaceutical grade CBD in pediatric onset drug resistant epilepsy with outcome measures including 50% seizure reduction, complete seizure freedom, improved QOL. A total of 36 studies were identified including 6 randomized controlled trials and 30 observational studies. Overall CBD at a dose of 20 mg/kg/day was more effective than placebo in reducing seizure frequency by 50% (Relative Risk 1.74: 1.24–2.43). For one patient to achieve a 50% reduction in seizures the number of patient needed to treat was 8. In pooled data of 17 of the observational studies CBD at 20 mg/ kg/day resulted in 48.5% of patients achieving a 50% reduction in seizures (95% CI: 39.0–58.1%) while pooled data from 14 observational studies showed 8.5% of patients became seizure free (95% CI: 3.8–14.5%). Quality of life improved in 55.8% of patients (95% CI: 40.5–70.6%) while serious adverse events related to treatment with CBD was very low at 2.2% of patients (95% CI: 0.0–7.9%). From this data, the authors concluded that pharmaceutical grade CBD may reduce seizure frequency but other randomized controlled trials examining a more diverse group of epilepsy syndromes and other cannabinoids was needed [70].

To date, the evidence to support the use of cannabis in adults is minimal. STAR 1 is a phase 2A, randomized, double blind, placebo-controlled study that evaluated the safety and efficacy of synthetic transdermal CBD in adult patients with focal epilepsy. In this study 174 patients were randomized to receive either 195 mg CBD, 390 mg CBD or placebo via a transdermal patch. Patients who completed the 12-week study were able to continue into the 24-month open-label extension STAR 2 study (n = 171). In as of yet published data from these trials there was an increase in efficacy of transdermal CBD over 18 months. Median percentage change in seizure rates was −25% at 3 months, −40% at 6 months, −48% at 9 months, −52% at 12 months, −57% at 15 months and −55% at 18 months. The transdermal patch was well tolerated. Serious adverse events were as follows: seizures (n = 2) and increased anxiety (n = 1); one death was reported after the 15 month visit. In addition, no significant elevations in alanine aminotransferase and aspartate aminotransferase levels >3 times upper limit of normal were seen [71].

In comparing cannabis derived treatments to standard therapies, it is worthwhile to note that the STICLO group examining the effects of stiripentol in Dravet patients in a double blind randomized placebo controlled study showed that 15 (71%) patients had >50% seizure reduction (including nine free of clonic or tonic-clonic seizures) compared to only one (5%) on placebo (none were seizure free; stiripentol 95% CI 52.1–90.7 vs. placebo 0–14.6). Stiripentol's responder rate is therefore suggested to be superior to Epidiolex with a far lower placebo responder rate [72]. Similarly, in a double-blind, randomized, placebo-controlled trial of the anti-epileptic drug rufinamide in patients with Lennox-Gastaut syndrome, the median percentage reduction in total seizure frequency was greater in the rufinamide therapy group than in the placebo group (32.7 vs. 11.7%, p = 0.0015). There was also a difference (p < 0.0001) in tonic-atonic ("drop attack") seizure frequency with rufinamide (42.5% median percentage reduction) vs. placebo (1.4% increase). These findings are comparable with the results with Epidiolex. One also has to keep in mind that the median reduction of atonic seizures in the placebo group was markedly higher with the Epidiolex study suggesting potential bias [73].

Of note, the results from the study by McCoy et al. and the preliminary data from CARE-E study showed a much higher responder rate than those with pharmaceutical grade CBD. This apparent superiority of a CHE containing Δ9 -THC would be in keeping with the proposed entourage effect in which the various cannabinoids can act synergistically with one another [42, 44].


**The Future Population Health of the Industrialized Countries**

Pietro Iaquinta

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67819

#### Abstract

The more developed countries are experiencing an inexorable decline with respect to population. Aging is reaching intolerable levels in the economy, both from the active (available workers) and the passive (e.g. health costs, pensions) point of view, redesigning a worrying scenario for the near future. On the other hand, fertility in many countries, and particularly in Italy, reaches such low levels that the prospects of a recovery, in terms of quantity, now seem impractical, unless of socio-demographic upheavals rather unlikely. In this context, most likely, from the point of view of demographic and social, he is starting a new era in which the main actors on the global stage will certainly be different from those in the field today, with completely obscure scenarios and still in the making. Surely, however, this situation has generated fears and concerns about the future of the population, especially for some signals that in the course of 2015 were recorded in Italy, such as the surge in mortality, especially with regard to older ages, where some observers have linked this phenomenon to a reduction in public spending in the health sector, a situation that would have penalized, certainly, the older age groups. On closer analysis, however, we realize that, precisely due to aging of the population of elderly, quotas have gradually increased, causing a swollen available to die, with the same probability of death.

Keywords: population, health, labor market, fertility, development


**4.3 Adaptable areas of disruptions in the quality assurance monitoring and calibration in production process**

In **Table 3**, adaptable areas of disruptions in quality assurance monitoring was presented highlighting the responses of respondents. There are a lot of areas in intelligent manufacturing that disruptions has taken place. Some of the areas includes system design, implementation and monitoring. Areas covered in the study, 10 areas of disruptions was identified they include; process design, analytical technology, platform technology, operation technology, intelligent spindle system, sensor based control units, intelligent system powered psychometric system, 3d

#### **Table 3.**

*Adaptable Areas of Disruptions in Quality Assurance Monitoring for Intelligent Manufacturing.*

design system and intelligent sequencing system. This Process design is ranked 1st with RAI of 0.869; analytical technology is ranked 2nd with RAI value 0.786, platform technology with RAI 0.771 is ranked 3rd, operation technology is ranked 4th with RAI value of 0.754, intelligent spindle system also ranked 5th with RAI 0.732, sensor based control units ranked 6th, while intelligent system powered psychometric system and 3D design system and intelligent sequencing system were ranked 8th and 9th respectively with RAI values 0.631 and 0.579. In disruption that relates to intelligent manufacturing, there is always benefits often associated with paradigm shift in innovation technology. [36] opined that there are a lot of opportunities accrued to disruption that are beneficial although there is always negative resistance usually connected with a new change. There are risks associated with disruptions on account of new innovations often involved with the change.

rectification system RAI 0.771 is ranked 2nd, Effective design and production calibration system with RAI 0.769 ranked 3rd, Intelligent cost control system with RAI 0.754 ranked 4th, while Effective data extraction and transfer with RAI value of 0.754 is ranked 5th. However, Adequate machine part management with RAI 0.623 and Half live of machine parts with RAI value of 0.541 were ranked least with 8th

*Adapting Disruptive Applications in Managing Quality Control Systems in Intelligence…*

Developing quality control is one of the important phase of manufacturing process. Quality control of product is very significant to the users and manufacturers. Quality to the manufacturer borders about correct design, authentic system calibration. Quality to consumer refers to manufactured product meeting users demand and expectation, therefore subjective in nature. ENQA (2009)in an adaptive study on standard and guidelines for quality assurance posited that there should be common reference point for quality assurance, keeping of quality register, procedure for quality assurance, keeping of quality register, documentation of procedure for the recognition of quality qualification and exchange of view among quality personnel. This could be encapsulated as a quality culture which should be keenly observed. Quality culture should be maintained so as to create a healthy production environment which guarantees customers production satisfaction. [40, 41] submitted further that quality culture would fine tune quality control value in a product system and this will lead to the reduction of political and geographical barrier). There are parameters that controls production in manufacturing industries, some of them includes: specification marketing, scheme and specification from purchasing units and agencies. Moreover, quality calibration at the outset of a manufacturing process usually ensures that quality product emerge from production system. Also, adoption of simple inspection table, and adoption of basic principles of sampling through sampling lot are cutting edge techniques that facilitates adoption of quality culture in product production, this toes the line of submissions

**4.5 Issues and challenges involved in adapting quality control systems in**

In this section challenges involved in the adapting of disruption application in intelligent manufacturing is outlined in **Table 5**. There are methods that could be used to control quality during manufacturing process [20, 21, 43] alluded that discrepancies in the document and. Process involved in manufacturing could be

**Issues and challenges PM Rank QCO Rank PS Rank ICTO Rank** Machine–machine interaction 0.865 2nd 0.852 2nd 0.785 1st 0.773 1st Man–machine interaction 0.873 1st 0.869 1st 0.721 2nd 0.653 2nd Data quality 0.762 4th 0.754 4th 0.720 3rd 0.589 3rd Cyber-security 0.771 3rd 0.771 3rd 0.698 4th 0.554 5th Spare part management 0.762 4th 0.732 5th 0.657 5th 0.467 6th Data Acquisition/Storage 0.657 5th 0.631 6th 0.589 6th 0.573 4th Training Challenges 0.634 6th 0.543 7th 0.568 7th 0.457 7th Testing cost & complexity 0.537 7th 0.557 7th 0.431 8th 0.456 8th

*Legend: Production Manager-PM; Quality Control Officer-QCO, Production Supervisor-PS;*

*ICT Officer-Information Communication Technology Officer.*

*Challenges involved in Adapting Quality Control System.*

and 9th position respectively.

*DOI: http://dx.doi.org/10.5772/intechopen.93979*

in [20, 42].

**Table 5.**

**69**

**intelligent manufacturing**

However, any visionary organization should learn how to strategize in situation of associated risks mitigation. Intelligent manufacturing disruption has impacted strategic aspect of intelligent manufacturing that is changing the trend of games in product manufacturing. For instance, the following areas of intelligent manufacturing has been duly impacted; economy of product, economy of value chain, demand for product and changing faces of product as supported in [36, 37]. The associated risk in the disruption in intelligent manufacturing was modelled by [37–39] for monitoring of systemic sequencing of operation in product manufacturing. Disruption risk and pattern was modelled in [37] with Poisson ump process using random multiple system. Similarly parameters were sequenced and stochastically correlated to monitor quality diffusion process. However, internet of things (IoT), cyber-physical system, logistic 4.0, manufacturing 4.0, and hospital 4.0 are some of the aspect of disruption in intelligent manufacturing that formed the embodiment of application that has enhanced product production and manufacturing.


• **Initialization**

Firstly, whole vector of initial population is assigned any arbitrary assessment [21] starting with its equivalent state:

$$X\_{j,i}^{(0)} = X\_j^{\min} + \mu\_j (X\_j^{\max} - X\_j^{\min}), \tag{2}$$

where μ*j* represents uniformly dispersed arbitrary numeral initialize with the array of [0, 1], generates novel for all value of *Xmin j* and *Xmax j* are representing the uppermost and lowermost limits of the jth parameter, correspondingly.


**1. Introduction**

Pediatric Adamantinomatous Craniopharyngiomas (ACPs) are histologically benign brain tumors that often follow an aggressive clinical course. The tumors are most commonly centered in the suprasellar region and are believed to develop from remnants of Rathke's pouch. Radiologically and grossly, these tumors appear as mixed solid and cystic lesions often with areas of calcification (Figure 1). Histologically, ACPs are heterogeneous tumors of epithelial origin [1,2]. The classic features consist of palisading epithelium, stellate cells, nodules of anuclear "ghost cells" and "wet keratin" as well as large areas of regressive changes (i.e., inflammation and calcifications, multinucleated giant cells, hemosiderin deposits, cholesterol clefts) [1] (Figure 2). Their proximity to critical neurological and vascular structures often confers significant neuroendocrine morbidity on patients [3]. Surgery remains the primary treatment strategy, but can result in significant morbidity, specifically damage to the hypothalamus, pituitary and optic apparatus, which results in long-term sequelae that can greatly impact a child's quality of life [4–6]. In an era of personalized medicine and targeted therapies,

*J. Clin. Med.* **2020**, *9*, 519

ACP remains resistant to such advances. On the other hand, recent case reports of the response of papillary craniopharyngioma, a different tumor of the suprasellar region, to BRAF inhibitors have elucidated the great potential of targeted therapies in treating these tumors [7,8]. As a result, recent years have witnessed significant efforts to fully elucidate the genomic, transcriptomic and proteomic make-up of ACP in an attempt to identify potential therapeutic targets for the treatment of this disease [9–15].

E

**Figure 1.** Classic histopathological findings in adamantinomatous craniopharyngioma: (**A**) H&E stained sections showing an epithelial tumor with palisading cells with aggregates of 'wet' keratin; (**B**) higher magnification view demonstrating keratinized 'ghost cells'; (**C**) Higher magnification view demonstrating calcifications and stellate reticulum; (**D**) Immunohistochemical staining for Beta-catenin that is nuclear positive in a subset of tumor cells. (**E**) The surrounding brain parenchyma shows extensive gliosis with Rosenthal fibers.

**Figure 2.** Computed Tomography (**Left**) andMagnetic resonance Imaging (**Right**) images from the same patient of a classic example of an adamantinomatous craniopharyngioma. This typical tumor is centered in the suprasellar region with mixed solid and cystic areas as well as areas of calcification as seen on the CT.


**Zinc-Based Nanomaterials for Diagnosis and Management of Plant Diseases: Ecological Safety and Future Prospects**

**Anu Kalia 1,\* , Kamel A. Abd-Elsalam 2 and Kamil Kuca 3,\***

Received: 22 September 2020; Accepted: 10 October 2020; Published: 13 October 2020

**Abstract:** A facet of nanorenaissance in plant pathology hailed the research on the development and application of nanoformulations or nanoproducts for the effective management of phytopathogens deterring the growth and yield of plants and thus the overall crop productivity. Zinc nanomaterials represent a versatile class of nanoproducts and nanoenabled devices as these nanomaterials can be synthesized in quantum amounts through economically affordable processes/approaches. Further, these nanomaterials exhibit potential targeted antimicrobial properties and low to negligible phytotoxicity activities that well-qualify them to be applied directly or in a deviant manner to accomplish significant antibacterial, antimycotic, antiviral, and antitoxigenic activities against diverse phytopathogens causing plant diseases. The photo-catalytic, fluorescent, and electron generating aspects associated with zinc nanomaterials have been utilized for the development of sensor systems (optical and electrochemical biosensors), enabling quick, early, sensitive, and on-field assessment or quantification of the test phytopathogen. However, the proficient use of Zn-derived nanomaterials in the management of plant pathogenic diseases as nanopesticides and on-field sensor system demands that the associated eco- and biosafety concerns should be well discerned and effectively sorted beforehand. Current and possible utilization of zinc-based nanostructures in plant disease diagnosis and management and their safety in the agroecosystem is highlighted.

**Keywords:** ecotoxicity; nanomaterial; nanosensors; phytopathogens; zinc