**7.1 Clinical rationale for omega-3 FAs therapy in SAH**

The theoretical framework described above provides scientific rationale for future clinical trials of omega-3 FAs in SAH patients. The disappointing results of RCTs of isolated pharmaceutical interventions in SAH could be overcome if a translational approach is correctly implemented [8]. In support of this notion, the recently published phase 3 REDUCE-IT trial provided a robust demonstration of the clinical efficacy and therapeutic potential of EPA to reduce cardiovascular events in chronic cardiovascular (CV) patients with hypertriglyceridemia [57]. Obviously, there are major differences between patients with chronic CV disease and hypertriglyceridemia and patients with SAH. Nevertheless, the considerable clinical benefits of EPA observed in patients with CV disease (who were already on statin therapy) may be due not only to the triglyceride-lowering effect of EPA. Interestingly, the results of the REDUCE-IT trial resemble those of the GISSI-Prevenzione trial conducted 20 years ago, in which a low-dose oral treatment of EPA plus DHA significantly reduced CV morbimortality in patients who had suffered a recent myocardial infarction and were already on aspirin treatment [58].

Minor changes in overall membrane FAs composition and the increase in local production of longer-acting SPM R-epimers after combined treatment with omega-3 FAs and aspirin or statins are likely to mediate a wide variety of biological effects and have a profound impact on cellular and multi-organ function [15]. Indeed, emerging evidence clearly indicates a strong association between a higher omega-3 index and major health benefits (reduced risk of both CV and all-cause mortality) over the long term [21]. However, the acute and critical nature of SAH imposes a particularly demanding therapeutic challenge as the homeostatic disturbances in the brain and other vital organs must be effectively addressed in the short term. An intervention based exclusively on oral supplementation with omega-3 FAs is unlikely to be fully effective on its own in the clinical context of SAH. However, the superiority of parenteral administration over oral or enteral administration of omega-3 FAs has been reliably demonstrated in short-term interventions [17, 59]. Parenteral administration of omega-3 FAs allows rapid delivery of higher doses of EPA and DHA without bioavailability issues and does not depend on the patient's clinical condition. Indeed, the incorporation profiles of EPA and DHA in the transport and functional pools after a single parenteral dose are equivalent to up to several weeks of oral supplementation. EPA and DHA appear in PBMCs as rapidly as 6 hours after a single parenteral dose, thus highlighting the ability of parenterally administered omega-3 FAs to easily reach the innate immune system [59]. The concentration of omega-3 FAs in the main plasmatic fraction that supplies the brain and other vital organs (the NEFA pool) also increases rapidly after a single parenteral dose [17, 60]. Thus, the SPM precursors EPA and DHA seem to be rapidly and widely available to activate resolution of inflammation on demand in different organs after parenteral administration. Therefore, parenteral administration may be the most efficient way to deliver omega-3 FAs during the acute stage of SAH. This novel therapy is in accordance with the concept of pharmaconutrition, in which key nutrients are utilized as pharmacological agents and delivered in appropriate doses via the most efficient administration route [61]. Oral or enteral administration may be suitable for medium- or long-term treatment when the patient's gastrointestinal function has completely recovered.

#### **8. Omega-3 FAs dosage for clinical use**

A regular supplementation dose for healthy subjects defined by several health associations worldwide is around 500–750 mg/day of EPA plus DHA and can be achieved by consuming a regular diet that contains two portions of fatty fish per week [62]. Therapeutic anti-inflammatory doses of EPA plus DHA are usually considered to be above 2 g/day [25]. A daily dose of at least 1 g EPA plus DHA/ day (EPA > 60% DHA) has been shown to be effective in patients with depressive

**245**

**9.2 Clinical studies**

*Aneurysmal Subarachnoid Hemorrhage and Resolution of Inflammation*

disorders [22]. EPA doses above 1.8 g/day seem to be required to produce clinically meaningful effects on endothelial and vascular function [63]. In patients with age-related cognitive decline, 900 mg DHA/day improved learning and memory function [64]. Importantly, omega-3 FAs doses can be significantly reduced by decreasing the dietary intake of omega-6 FAs. This fact likely explains the notably different dosages of EPA required to obtain beneficial outcomes in patients with chronic CV disease in a Japanese trial (1.8 g/day) and the REDUCE-IT trial (4 g/

The therapeutic dose of parenteral fish oil (FO) to complement total parenteral nutrition (TPN) is of 0.1–0.2 g of FO/kg/day [59]. This dosage is equivalent to 1–2 ml/

Bioavailability refers to both the speed of absorption and the quantity of the substance absorbed in the gastrointestinal tract. The bioavailability of omega-3 FAs oral formulations should be carefully considered as it may have direct clinical implications [65]. The bioavailability of EPA and DHA depends on the chemical form in which they are bound (phospholipids > triglycerides > free fatty acids > ethyl esters) as well as their Galenic form (i.e., microencapsulation, emulsification) and also matrix effects (capsule ingestion with concomitant content of food, fat content in food). Galenic form and matrix effects are the most important factors that influence the bioavailability of EPA and DHA. Thus, administration of high-quality pharmaceutical formulations with fatty meals is necessary to ensure the effective-

To date, only two preclinical studies of omega-3 FAs in experimental models of SAH have been published. Yin et al. suggested that pre-treatment with omega-3 FAs by oral gavage elicited anti-inflammatory and anti-apoptotic effects in a rat model of SAH [66]. Zhang et al. showed intravenous administration of DHA may prevent oxidative stress-induced apoptosis by improving mitochondrial dynamics in a rat model of SAH induced by endovascular perforation [67]. However, the scarcity of preclinical studies on omega-3 FAs in SAH contrasts with the large number of experimental studies on ischemic stroke. The effects of omega-3 FAs (or specific derivatives) in neural tissue have been widely examined in experimental ischemiareperfusion models [55, 68, 69]. These studies have consistently shown that omega-3 FAs significantly reduce cerebral infarction volume by around 40–50% and are associated with a drastic decrease in the neuroinflammatory response [70, 71]. Interestingly, the long-term neurobehavioral recovery in experimental models of ischemic stroke is associated with neuroprotective effects of DHA on both gray and white matter [55]. It is noteworthy that one of these studies used a specific

A limited number of omega-3 FAs interventional studies have been performed in SAH patients [13, 72–74]. The main characteristics and findings of these studies

**9. Experimental models and clinical interventional studies** 

*DOI: http://dx.doi.org/10.5772/intechopen.88297*

day) conducted in 11 Western countries [48, 57, 63].

kg/day of a specific FOLE that contains 10 g of FO/100 ml.

**8.1 Bioavailability of omega-3 FAs oral formulations**

ness of oral therapy.

**of omega-3 FAs in SAH**

FOLE that is widely approved for clinical use [70].

**9.1 Experimental models**

*Aneurysmal Subarachnoid Hemorrhage and Resolution of Inflammation DOI: http://dx.doi.org/10.5772/intechopen.88297*

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

patient's gastrointestinal function has completely recovered.

A regular supplementation dose for healthy subjects defined by several health associations worldwide is around 500–750 mg/day of EPA plus DHA and can be achieved by consuming a regular diet that contains two portions of fatty fish per week [62]. Therapeutic anti-inflammatory doses of EPA plus DHA are usually considered to be above 2 g/day [25]. A daily dose of at least 1 g EPA plus DHA/ day (EPA > 60% DHA) has been shown to be effective in patients with depressive

**8. Omega-3 FAs dosage for clinical use**

of RCTs of isolated pharmaceutical interventions in SAH could be overcome if a translational approach is correctly implemented [8]. In support of this notion, the recently published phase 3 REDUCE-IT trial provided a robust demonstration of the clinical efficacy and therapeutic potential of EPA to reduce cardiovascular events in chronic cardiovascular (CV) patients with hypertriglyceridemia [57]. Obviously, there are major differences between patients with chronic CV disease and hypertriglyceridemia and patients with SAH. Nevertheless, the considerable clinical benefits of EPA observed in patients with CV disease (who were already on statin therapy) may be due not only to the triglyceride-lowering effect of EPA. Interestingly, the results of the REDUCE-IT trial resemble those of the GISSI-Prevenzione trial conducted 20 years ago, in which a low-dose oral treatment of EPA plus DHA significantly reduced CV morbimortality in patients who had suffered a recent myocardial infarction and were already on aspirin treatment [58]. Minor changes in overall membrane FAs composition and the increase in local production of longer-acting SPM R-epimers after combined treatment with omega-3 FAs and aspirin or statins are likely to mediate a wide variety of biological effects and have a profound impact on cellular and multi-organ function [15]. Indeed, emerging evidence clearly indicates a strong association between a higher omega-3 index and major health benefits (reduced risk of both CV and all-cause mortality) over the long term [21]. However, the acute and critical nature of SAH imposes a particularly demanding therapeutic challenge as the homeostatic disturbances in the brain and other vital organs must be effectively addressed in the short term. An intervention based exclusively on oral supplementation with omega-3 FAs is unlikely to be fully effective on its own in the clinical context of SAH. However, the superiority of parenteral administration over oral or enteral administration of omega-3 FAs has been reliably demonstrated in short-term interventions [17, 59]. Parenteral administration of omega-3 FAs allows rapid delivery of higher doses of EPA and DHA without bioavailability issues and does not depend on the patient's clinical condition. Indeed, the incorporation profiles of EPA and DHA in the transport and functional pools after a single parenteral dose are equivalent to up to several weeks of oral supplementation. EPA and DHA appear in PBMCs as rapidly as 6 hours after a single parenteral dose, thus highlighting the ability of parenterally administered omega-3 FAs to easily reach the innate immune system [59]. The concentration of omega-3 FAs in the main plasmatic fraction that supplies the brain and other vital organs (the NEFA pool) also increases rapidly after a single parenteral dose [17, 60]. Thus, the SPM precursors EPA and DHA seem to be rapidly and widely available to activate resolution of inflammation on demand in different organs after parenteral administration. Therefore, parenteral administration may be the most efficient way to deliver omega-3 FAs during the acute stage of SAH. This novel therapy is in accordance with the concept of pharmaconutrition, in which key nutrients are utilized as pharmacological agents and delivered in appropriate doses via the most efficient administration route [61]. Oral or enteral administration may be suitable for medium- or long-term treatment when the

**244**

disorders [22]. EPA doses above 1.8 g/day seem to be required to produce clinically meaningful effects on endothelial and vascular function [63]. In patients with age-related cognitive decline, 900 mg DHA/day improved learning and memory function [64]. Importantly, omega-3 FAs doses can be significantly reduced by decreasing the dietary intake of omega-6 FAs. This fact likely explains the notably different dosages of EPA required to obtain beneficial outcomes in patients with chronic CV disease in a Japanese trial (1.8 g/day) and the REDUCE-IT trial (4 g/ day) conducted in 11 Western countries [48, 57, 63].

The therapeutic dose of parenteral fish oil (FO) to complement total parenteral nutrition (TPN) is of 0.1–0.2 g of FO/kg/day [59]. This dosage is equivalent to 1–2 ml/ kg/day of a specific FOLE that contains 10 g of FO/100 ml.

#### **8.1 Bioavailability of omega-3 FAs oral formulations**

Bioavailability refers to both the speed of absorption and the quantity of the substance absorbed in the gastrointestinal tract. The bioavailability of omega-3 FAs oral formulations should be carefully considered as it may have direct clinical implications [65]. The bioavailability of EPA and DHA depends on the chemical form in which they are bound (phospholipids > triglycerides > free fatty acids > ethyl esters) as well as their Galenic form (i.e., microencapsulation, emulsification) and also matrix effects (capsule ingestion with concomitant content of food, fat content in food). Galenic form and matrix effects are the most important factors that influence the bioavailability of EPA and DHA. Thus, administration of high-quality pharmaceutical formulations with fatty meals is necessary to ensure the effectiveness of oral therapy.
