Arachidonic acid therapy for the treatment of neutropenia

Abstract

The disclosure provides methods and compositions for alleviating neutropenia resulting from a cytotoxic therapy in a cancer patient. The method comprises administering a therapeutically effective amount of an arachidonic acid composition to the patient prior to initiation of, or in conjunction with, the cytotoxic therapy, preferably in combination with one or more myeloid growth factors, and still more preferably wherein the arachidonic acid composition is or comprises a pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity.

Description

ARACHADONIC ACID THERAPY FOR THE TREATMENT OF NEUTROPENIACROSS REFERENCE TO RELATED APPLICATION

[0001] This Application claims the benefit of U.S. Provisional Application Serial No.63 / 677971 , filed July 31, 2024; the contents of which are hereby incorporated in their entirety. FIELD

[0002] The disclosure provides methods and compositions for alleviating neutropenia and / orco-morbidities thereof resulting from a cytotoxic therapy in cancer patients. The method comprises administering a therapeutically effective amount of an arachidonic acid composition to the patient prior to, or in conjunction with, initiation of the cytotoxic therapy, preferably in combination with one or more myeloid growth factors, and still more preferably wherein the arachidonic acid composition is or comprises a pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity. BACKGROUND

[0003] Despite significant advances in oncology and anti-cancer therapies such as immunecheckpoint inhibitors and targeted therapies, chemotherapeutic agents still play a pivotal role in the management of many solid tumors and hematological malignancies. Rapoport et al. (2023) Supportive Care in Cancer 31:628. Indeed, combination immunotherapy using immune- checkpoint inhibitors with chemotherapy has been widely employed in an effort to improve patient response rates and help overcome primary resistance to immunotherapy alone. Bossi et al. (2021) J. Immunotherapy Cancer 9(8). Unfortunately, however, this strategy has shown increased effectiveness only at the price of higher toxicity. Id. As such, chemotherapy-related adverse events remain high, and are still associated with substantial morbidity and mortality. Rapoport, supra; Kuderer et al. (2022) Nat Rev Clin Oncol 19(11):681-697.

[0004] One of the most frequent side effects of cytotoxic agents is neutropenia, whichdramatically increases the risk of infection. See, e.g.. Tralongo et al. (2020) Tumori Journal 106(4):273–280. Febrile neutropenia is the most serious manifestation of neutropenia and a key driver of chemotherapy dose delays and / or reductions. Id.; Klastersky et al. (2016) Ann Oncol 27:v111–v118. The requisite modification in dose intensity may impact treatment efficacy, and the resulting neutropenic fevers frequently lead to hospital admissions with significant mortality due to infection-related complications. Id. Moreover, certain co-morbidities (e.g. diarrhea and mucositis) associated with each neutropenic cycle also increase the risk of infectious - 1 - 1104747404\8\AMERICAScomplications. Furthermore, and more generally, febrile neutropenia triggers significant additional costs attributable to the increased use of antibiotics and antiviral therapies as well as unplanned hospitalizations. Kasi et al. (2018) Drugs 78(7):737–745.

[0005] The prophylactic use of myeloid growth factors such as the colony-stimulating factorsG-CSF and GM-CSF in patients with heightened risk can reduce the severity and duration of febrile neutropenia. Unfortunately, however, the mortality rates of febrile neutropenia are still reported to be 10‒30% (Al-Tawfiq et al., J Infect Public Health, 2019;12(3):364-366; Auesomwang et al., J Med Assoc Thai 2018; 101 (2): 173-180; Parodi et al., PLoS One, 2019, 14(10):e0224299; Weerasubpong et al., J Med Assoc Thai 2016, 99 (Suppl 8):S53-S62). Clearly, then, more effective treatments are sorely needed.

[0006] Nutritional interventions have been suggested as a means for alleviating certain sideeffects (e.g. gastrointestinal toxicity) resulting from chemotherapy. For example, glutamine, ω-3 polyunsaturated fatty acids, and probiotics / prebiotics have been suggested as therapeutic agents for the modulation that of GI toxicity related to cancer treatments (Xue et al., Journal of Parenteral and Enteral Nutrition 2011, Vol. 35(1), 74-90). Similarly, Wang (Stem Cell Reports 2020, 15: 374–388) has suggested that arachidonic acid promotes regeneration of radiation-damaged intestinal epithelial cells, thus contributing to regenerative mechanisms of the intestine.

[0007] Conversely, however, Kallianan et al. (Int. J. Mol. Sci. 2022, 23:5332) teach thatomega-6 fatty acids are detrimental in the treatment of gastrointestinal toxicities. Indeed, Kaliannan et al. teach that omega-6 (ω-6) and omega-3 (ω-3) polyunsaturated fatty acids (PUFA) have opposing effects on the gut microbiome and that a decreased ω-6 / ω-3 PUFA ratio reduces gastrointestinal toxicity and associated changes in the gut microbiome. Moreover, the ω-6 series of eicosanoids are known to be more pro-inflammatory and pro-proliferative to tumors than their ω-3 counterparts, see e.g., D’Angelo et al. Nutrients 2020, 12:2751; and there are numerous reports suggesting a role for ω-6 fatty acids in cancer and carcinogenesis, see e.g., Angelucci et al., Endocrine-Related Cancer 2008, 15: 91–100; Yarla et al., Seminars in Cancer Biology 2016, 40–41, 48–81; Wang et al., Signal Transduction and Targeted Therapy (2021) 6:94; Finetti et al., Biology 2020, 9, 434; Wen, et al. Oncogene 2013, volume 32, pages 160–170; Sakai et al. (BMC Cancer 2012, 12:606).

[0008] As such, the potential impact of directly administering an omega-6 fatty acid such asarachidonic acid to a cancer patient would seem at best uncertain, if not outright contraindicated. Accordingly, and despite extensive research, effective treatments for prevention or protection against neutropenia and other side effects of chemotherapy remain elusive. - 2 - 1104747404\8\AMERICAS

[0009] Fortunately, as will be apparent from the detailed description that follows, the presentdisclosure provides for these and other needs. SUMMARY

[0010] In a first aspect, provided is a pharmaceutical composition,arachidonic acid of high purity and / or one or more esters thereof of high purity; and one or more pharmaceutically acceptable excipients independently selected from the group consisting of an emulsifying agent, a pharmaceutically acceptable oil or pharmaceutically acceptable wax, and a co-solvent; and additionally comprising an optional stabilizer.

[0011] In embodiments of the first aspect and embodiments thereof, the pharmaceuticalcomposition is an oral pharmaceutical composition. In embodiments, the pharmaceutical composition is in a capsule, in a gummy, or in granular form, preferably in a soft gelatin capsule. In embodiments, the pharmaceutical composition is a liquid. In embodiments, the pharmaceutical composition is a liquid in a capsule.

[0012] In a second aspect, provided is a method for alleviating neutropenia resulting from acytotoxic therapy in a cancer patient, the method comprising: administering a therapeutically effective amount of an arachidonic acid composition or of a therapeutically effective amount of the pharmaceutical composition of the first aspect (or of any embodiments provided herein) to the patient at least 3 days prior to initiation of the cytotoxic therapy. Also a method for alleviating neutropenia and / or co-morbidities thereof resulting from a cytotoxic therapy in a cancer patient is provided, the method comprising: administering a therapeutically effective amount of an arachidonic acid composition to the patient at least 3 days prior to initiation of the cytotoxic therapy. In embodiments, the co-morbidity is anemia. In embodiments, the co-morbidity is gastrointestinal toxicity.

[0013] In a third aspect, a method for alleviating chemotherapy-induced hair loss, is provided,the method comprising: administering a therapeutically effective amount of an arachidonic acid composition to the patient at least 3 days prior to initiation of the chemotherapy. In embodiments, the arachidonic acid composition is provided as a pharmaceutical composition according to the first aspect above or any embodiments thereof provided herein.

[0014] In a fourth aspect, a method of treating alopecia in a patient in need thereof is provided,the method comprising administering a therapeutically effective amount of an arachidonic acid composition to the patient. In embodiments, the arachidonic acid composition is provided as a - 3 - 1104747404\8\AMERICASpharmaceutical composition according to the first aspect above or any embodiments thereof provided herein.

[0015] In a fifth aspect, provided is a method for enhancing bone marrow mobilization indonors for stem cell transplant prior to retrieval, for acceleration of bone marrow (in embodiments neutrophil) engraftment in bone marrow transplant recipients, and / or for treatment of genetic neutropenias, (e.g. Severe Congenital Neutropenia (Kostmann Disease)), the method comprising: administering a therapeutically effective amount of an arachidonic acid composition or of the pharmaceutical composition of the first aspect (or any embodiments thereof provided herein) to a patient in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 provides the effect on neutrophil recovery in animals that consumed purifieddiet with 3% (w / w) ARASCO® oil and 4% (w / w) soybean oil added (ARD) prior to chemotherapy (5-FU), compared to standard diet, according to Example 1b, Group 1.

[0017] Figures 2a, 2c, and 2d, respectively, provide neutrophil, red blood cell (RBC), andhemoglobin (HGB) counts, with and without chemotherapy treatment, in mice fed control diet, ARD (purified diet with 3% ARASCO® oil and 4% soybean oil added) diet, ARA (purified diet with 3% ARASCO® powder and 4% soybean oil added) diet, and AA FFA (arachidonic acid, free fatty acid) diet, according to Example 7. Figure 2b shows a blown-out version of the data from Figure 2a for chemotherapy-treated mice.

[0018] Figures 3a-3e provide neutrophil, white blood cell (WBC), lymphocyte, red blood cell(RBC), and hemoglobin (HGB) counts, respectively, in control diet (purified diet with 7% w / w soybean oil) and ARD (purified diet + 3% ARASCO® oil and 4% soybean oil added) diet fed mice before and after chemotherapy, according to Example 8.

[0019] Figures 4a-4b provide % LSK in Lin- and # LSK (FIG. 4a), and platelet count (FIG.4b) in control diet and ARD fed mice after chemotherapy, according to Example 9.

[0020] Figure 5A provides hair growth visual score for control diet 1 v. control diet 1 with 3%(w / w) ARASCO oil and 4% soybean oil added (ARD 1), according to Example 6a.

[0021] Figure 5B provides photographs of mice on control diet v. ARD, according to Example6b. - 4 - 1104747404\8\AMERICASINCORPORATION BY REFERENCE

[0022] All publications, patents, and patent applications mentioned in this specification areherein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0023] The toxicity of cancer chemotherapy is among the most important factors limiting itsuse. The dangerous and debilitating nature of febrile neutropenia in particular frequently leads to dose reductions, delays, and cessation of cancer treatment, and is associated with still- unacceptable levels of morbidity. Clearly there are no benefits of cancer therapy if the treatment is worse than the cure. Thus, the development of intervention strategies that can help cancer patients recover more rapidly from neutropenia, prevent (or protect) them from progressing to febrile neutropenia, and / or simply avoid neutropenia altogether, are still very much needed. Fortunately, the present disclosure provides such an intervention strategy.

[0024] The present disclosure also provides pharmaceutical compositions, including self-emulsifying drug delivery systems (SEDDS), of arachidonic acid of high purity and / or one or more esters thereof of high purity. SEDDS are lipid-based formulations combining active ingredient with additives that together help disperse the hydrophobic components in the aqueous environment of the gastro-intestinal tract after they are taken orally. SEDDS are an important way to improve the oral absorption of highly lipophilic active ingredients with poor aqueous solubility. Following oral administration, SEDDS rapidly emulsify and rapidly disperse in gastrointestinal fluids, yielding oil-in-water emulsions (such as micro- or nanoemulsions) that facilitate digestion and absorption of the hydrophobic active ingredient.

[0025] A limitation of the currently used form of arachidonic acid (for example, ARASCO®Oil) is that it has only about 40% potency (i.e. 40% arachidonic acid derived from its various forms in the composition), it comprises many other compounds, and it may not have optimal properties for oral absorption. Also needed then are pharmaceutical compositions comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, for example, in a SEDDS formulation. A high-purity arachidonic acid product allows a lower quantity of the composition to be administered compared to products made using ARASCO® Oil, which is beneficial in terms of the amount of product consumed (commonly referred to as “pill-burden”) as well as reducing the quantity of non-active material consumed by the patient which is not providing any functionality to the formulation. - 5 - 1104747404\8\AMERICAS

[0026] The oral formulation of high-purity arachidonic acid will still require a high oral doseper dosage unit. For an orally-administered oil like arachidonic acid, a non-emulsifying composition presents potential risks of local irritation, poor tolerability, and high variability in absorption following an oral dose. Each of these risks can severely impact safety, efficacy and / or patient compliance with a pharmaceutical product. These risks may all be reduced by using a SEDDS formulation approach. A SEDDS pharmaceutical composition provided herein may improve the systemic blood levels of arachidonic acid by 1) improving the dispersion of arachidonic acid in the gastro-intestinal tract, presenting it to the body in a more absorbable form, and / or 2) facilitating absorption through rapid emulsification, as arachidonic acid may be dispersed faster compared to a neat (unformulated) form of arachidonic acid. Definitions

[0027] Unless otherwise defined, all terms of art, notations and other scientific terminologyused herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and / or parameters unless otherwise noted.

[0028] As used herein, the singular forms “a,” “an,” and “the” include the plural referents,including one or more, unless the context clearly indicates otherwise.

[0029] As used herein, “about” is understood by persons of ordinary skill in the art and mayvary to some extent depending upon the context in which it is used. The term “about” indicates and encompasses an indicated value and a range above and below that value that is recognized by those of ordinary skill in the art to provide an effect equivalent to that obtained from the specified value. In embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In embodiments, where indicated, the term “about” indicates the designated value ± one standard deviation of that value.

[0030] As will be understood by one skilled in the art, for any and all purposes, all rangesdisclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Furthermore, as will be understood by one skilled in the art, a range includes each - 6 - 1104747404\8\AMERICASindividual member. Thus, for example, a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth.

[0031] The term “combinations thereof” includes every possible combination of elements towhich the term refers.

[0032] The term “subject” or ‘patient” as used herein, refers to an individual or mammalhaving a disease or at elevated risk of having a disease (e.g., having or at elevated risk of having diabetes or cancer). The subject may be any mammal, including both a human and other mammals, e.g. an animal such as a rabbit, mouse, rat, or monkey. Human subjects are preferred.

[0033] The term “arachidonic acid” or “AA” as used herein, refers to a 20-carbon chainpolyunsaturated fatty acid having four cis (Z) double bonds at carbons 5, 8, 11, and 14 counting from the carboxyl end. Because the first double bond is located between carbon 6 and 7 counting from the methyl or omega (ω) end, AA is an omega-6 (n-6) polyunsaturated fatty acid. Specifically, “arachidonic acid” is a polyunsaturated fatty acid 20:4ω-6 or 20:4 (5,8,11,14). Arachidonic acid may also be referred to as “all-cis-5,8,11,14-eicosatetraenoic acid,” and has the International Union of Pure and Applied Chemistry (IUPAC) name: “(5Z,8Z,11Z,14Z)-icosa- 5,8,11,14-tetraenoicacid.” The chemical structure of arachidonic acid in a “hairpin” configuration is shown below. In embodiments, the arachidonicacid where “high purity” is as defined hereinafter. In embodiments, the arachidonic acid has a purity or potency of about 70% or less, about 60% or less, about 50% or less, about 40% or less, about 30% or less, or about 35% to about 45%. In some embodiments, arachidonic acid is in deuterated form, for example, as provided in Molchanova et al. Antioxidants (Basel) 2022 Mar 31;11(4):681.

[0034] As used herein, “arachidonic acid ester of high purity,” “high purity arachidonic ester,”and “one or more esters of arachidonic acid of high purity” refer to 1) arachidonic acid ester of high purity (wherein “high purity” is defined hereinafter),according to the following formula: - 7 - 1104747404\8\AMERICASwhere R is an alkyl group, as defi 2) “arachidonic acid glyceride of high purity, as defined hereinafter.For the avoidance of doubt, “arachidonic acid of high purity and / or one or more esters thereof of high purity” refers to arachidonic acid of high purity, a single ester of arachidonic acid of high purity, two or more different esters of arachidonic acid which are of high purity, a combination of arachidonic acid of high purity and a single ester of arachidonic acid of high purity, and a combination of arachidonic acid of high purity and two or more different esters of arachidonic acid which are of high purity. In embodiments, the arachidonic acid of high purity and / or one or more esters thereof of high purity is arachidonic acid of high purity. In embodiments, the arachidonic acid of high purity and / or one or more esters thereof of high purity is a single ester of arachidonic acid of high purity.

[0035] “Alkyl” means a linear or branched saturated monovalent hydrocarbon radical of oneto ten carbon atoms, in embodiments one to six carbon atoms, in embodiments one to four carbons, and in embodiments one to three carbons. In embodiments, alkyl is methyl, ethyl, propyl, 2-propyl, or butyl and the like. In embodiments, the alkyl is methyl or ethyl. In embodiments, the alkyl is ethyl.

[0036] The term “arachidonic acid glyceride of high purity” refers to a compound orcompounds according to any one or more of the following formulas:

[0037] As used herein “high purity” when referring to arachidonic acid, an arachidonic acidester, and an arachidonic acid glyceride, means the individual acid / ester / glyceride has a purity of about 70% or greater, about 75% or greater, about 80% or greater, about 85% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, or about 99% or greater as measured by GC. When “high purity” is used in the context of “a combination of arachidonic acid of high purity and one or more esters of arachidonic acid of high purity,” the purity is measured as the combined quantity of the arachidonic acid and the one or more esters of arachidonic acid within the total active component. In embodiments, the impurities for arachidonic acid glyceride of high purity may include arachidonic acid mono and / or - 9 - 1104747404\8\AMERICASdiglycerides where the glycerol portion is substituted with one or two fatty acid(s) other than arachidonic acid (such as palmitic acid, stearic acid, oleic acid, and linoleic acid). In embodiments, the impurities for arachidonic acid of high purity may include other long chain fatty acids, long chain unsaturated fatty acids, long chain compounds related to fatty acids (degradation products or process impurities), glycerol or mono-, di- or tri-glyceride

[0038] The term “arachidonic acid glyceride composition” refers to a compositiona) comprising one or more of the following: 1-AG, 2-AG, 1,2-AG, 1,3-AG, and 1,2,3-AG(hereinafter referred to as “Composition (a)”); b) optionally comprising arachidonic acid (hereinafter referred to as “Composition (b)”); andc) additionally comprising 1) arachidonic acid mono and / or diglycerides where the glycerolportion is substituted with one or two fatty acid(s) other than arachidonic acid (such as palmitic acid, stearic acid, oleic acid, and linoleic acid); and / or 2) free fatty acids (other than arachidonic acid) such as palmitic acid, stearic acid, oleic acid, and linoleic acid (hereinafter referred to as “Composition (c)”). In embodiments, arachidonic acid glyceride composition refers to arachidonic acid triglycerides and compositions thereof as provided in PCT / US2024 / 013511 the contents of which is hereby incorporated by reference in its entirety. In embodiments, arachidonic acid glyceride composition refers to a composition produced by and extracted from M. alpina. In embodiments, the arachidonic acid glyceride composition has a potency of about 70% or less, about 60% or less, about 50% or less, about 40% or less, about 30% or less, or about 35% to about 45% of arachidonic acid (derived from its various forms in the composition). In embodiments, the arachidonic acid glyceride composition has a purity of about 70% or less, about 60% or less, about 50% or less, about 40% or less, about 30% or less, or about 35% to about 45% of arachidonic acid (derived from its various forms in the composition). For example, “arachidonic acid glyceride composition” includes ARASCO® oil or powder and ARA Gold Oil AP (BASF) and the like.

[0039] The term “arachidonic acid composition” refers to a composition comprisingarachidonic acid of high purity and / or one or more esters thereof of high purity, and / or an arachidonic acid glyceride composition.

[0001] In embodiments, the “arachidonic acid of high purity and / or one or more esters thereofof high purity,” “arachidonic acid glyceride of high purity,” “arachidonic acid glyceride composition,” and the “arachidonic acid composition” of the present disclosure is the sole active ingredient (or sole active pharmaceutical agent) in the pharmaceutical composition. In embodiments, the “arachidonic acid of high purity and / or one or more esters thereof of high purity,” “arachidonic acid glyceride of high purity,” “arachidonic acid glyceride composition,” - 10 - 1104747404\8\AMERICASand the “arachidonic acid composition” of the present disclosure is the sole active ingredient (or sole active pharmaceutical agent) in a therapeutically effective amount in the composition. In embodiments, the “arachidonic acid of high purity and / or one or more esters thereof of high purity,” “arachidonic acid glyceride of high purity,” “arachidonic acid glyceride composition,” and the “arachidonic acid composition” of the present disclosure is the sole active ingredient (or sole active pharmaceutical agent) used in the treatment or suppression of disorders described herein. In embodiments, the “arachidonic acid of high purity and / or one or more esters thereof of high purity,” “arachidonic acid glyceride of high purity,” “arachidonic acid glyceride composition,” and the “arachidonic acid composition” of the present disclosure is the sole active ingredient (or sole active pharmaceutical agent) used in a therapeutically effective amount in the treatment or suppression of disorders described herein. In embodiments, the pharmaceutical compositions, comprising the “arachidonic acid of high purity and / or one or more esters thereof of high purity,” “arachidonic acid glyceride of high purity,” “arachidonic acid glyceride composition,” and the “arachidonic acid composition” of the present disclosure – can additionally comprise one or more other active ingredients (or sole active pharmaceutical agents) or can be sued in combination with one or more other active ingredients (or sole active pharmaceutical agents).

[0002] In embodiments, the arachidonic acid composition is or comprises an arachidonic acidglyceride composition. In embodiments, about 90% to about 99% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (a), about 0.5% to about 3.5% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (b) and / or Composition (c) . In embodiments, the % is % by weight. In embodiments, the % is area % (as measured, for example, by gas chromatography).

[0003] In embodiments, the arachidonic acid composition is or comprises an arachidonic acidglyceride composition. In embodiments, at least 90% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (a). In embodiments, at least 95% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (a). In embodiments, at least 96% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (a). In embodiments, at least 97% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (a). In embodiments, at least 98% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (a). In embodiments, at least 99% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (a). In embodiments, about 94% to about 99%, about 95% to about 99%, about 96% to about 99%, about 97% to about 99%, about 98% to about 99%, of the - 11 - 1104747404\8\AMERICASarachidonic acid glyceride that is in the arachidonic acid composition is Composition (a). In embodiments, the % is % by weight. In embodiments, the % is area % (as measured, for example, by gas chromatography).

[0004] In embodiments, the arachidonic acid composition is or comprises an arachidonic acidglyceride composition. In embodiments, about 0.5% to about 1.5% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (b) and / or Composition (c). In embodiments, about 0.5% to about 1.5% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (b) and / or Composition (c). In embodiments, about 0.5% to about 1.5% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (b) and / or Composition (c). In embodiments, about 0.7% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (b) and / or Composition (c). In embodiments, about 0.8% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (b) and / or Composition (c). In embodiments, about 0.9% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (b) and / or Composition (c). In embodiments, about 1.0% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (b) and / or Composition (c). In embodiments, about 1.1% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (b) and / or Composition (c). In embodiments, about 1.2% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (b) and / or Composition (c). In embodiments, about 1.3% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (b) and / or Composition (c). In embodiments, about 1.4% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (b) and / or Composition (c). In embodiments, about 1.5% of the arachidonic acid glyceride that is in the arachidonic acid composition is Composition (b) and / or Composition (c). In embodiments, the % is % by weight. In embodiments, the % is area % (as measured, for example, by gas chromatography).

[0005] In embodiments, the remaining content of the arachidonic acid glyceride composition,that is not arachidonic acid or a glyceride thereof, comprises oleic acid, palmitic acid, stearic acid, linoleic acid, gamma-linoleic acid, dihomo-gamma-linoleic acid, behenic acid, ligonoceric acid, and other fatty acids (preferably, wherein the oleic acid, palmitic acid, stearic acid, linoleic acid, gamma-linoleic acid, dihomo-gamma-linoleic acid, behenic acid, ligonoceric acid, and other fatty acids are in the form of or a majority of the content is in the form of triglycerides); where the arachidonic acid glyceride content and the remaining content total 100%. In some or any embodiments, the remaining content is as provided in the following table: - 12 - 1104747404\8\AMERICASFatty acid Range 1 Range 2oleic acid ~16-23% ~3-21.9%l iti id 7 10% 4 11%o a condition wherein a patient’sneutrophil count falls below a threshold needed for proper immune functionality. The normal range of neutrophils in a healthy adult is generally between 2,500 and 7,000 neutrophils per microliter of blood, such that any number below 2,500 puts a patient at risk of adventitious infection. Clinical neutropenia is often defined as an absolute neutrophil count (ANC) of <500 neutrophils / mcL or an ANC of <1,000 neutrophils / mcL and a predicted decline ≤500 neutrophils / mcL over the next 48 hours. Neutropenia can progress to febrile neutropenia (FN; ≥38.3°C orally or ≥38.0°C duration over 1 hour), which often requires prolonged hospitalization and broad-spectrum antibiotic use. In embodiments, symptoms of neutropenia may include, but are not limited to fever (febrile neutropenia), fatigue, sore throat (pharyngitis), swollen lymph nodes, mouth sore, pain, swelling and rash at an infection site, diarrhea, and burning with urination or other urinary symptoms (urgency, frequency).

[0007] Thus, the phrase “alleviating neutropenia” as used herein, refers to stabilizing and / orincreasing a patient’s neutrophil count, avoiding and / or resolving neutropenia, avoiding progression to febrile neutropenia, resolving febrile neutropenia, and / or to alleviating at least one symptom of neutropenia.

[0008] As detailed herein, the subject pharmaceutical compositions may also findadvantageous use in treating certain co-morbidities of neutropenia, including gastrointestinal toxicities commonly resulting from cytotoxic therapies.

[0009] The term “gastrointestinal toxicity” as used herein, refers to damage to thegastrointestinal system resulting from a therapeutic intervention for a disease or disorder and symptoms suffered by an individual as a result of the damage. In embodiments, symptoms of “gastrointestinal toxicity” may include, but are not limited to nausea, vomiting, diarrhea, loss of appetite, malabsorption, abdominal pain, constipation, rectal bleeding, mucositis, and mouth sores. - 13 - 1104747404\8\AMERICAS

[0010] Thus, the phrase “alleviating gastrointestinal toxicity” as used herein, refers toalleviating at least one symptom of gastrointestinal toxicity resulting from therapeutic medical intervention comprising cytotoxic therapy.

[0011] The term “cytotoxic therapy” as used herein, refers to a medical intervention that istoxic to cells. Typically, a “cytotoxic therapy” is administered with the objective of killing disease cells e.g., cancer cells. Unfortunately, while a “cytotoxic therapy” may ultimately kill disease cells and thereby cure a disease e.g., cancer, or send it into remission, cytotoxic therapies may also kill or damage otherwise healthy cells causing symptoms and suffering for the individual experiencing the “cytotoxic therapy.” In embodiments, the “cytotoxic therapy” is chemotherapy and the symptoms and suffering are the result of “neutropenia.”

[0012] The term “disease,” or “disease or disorder” as used herein, refers any condition ordisorder that damages or interferes with the normal function of a cell, tissue, or organ. In embodiments, the disease or disorder is neutropenia. In embodiments, the disease or disorder is a genetic neutropenia, e.g. Severe Congenital Neutropenia (Kostmann Disease). In embodiments, the disease or disorder is gastrointestinal toxicity. In embodiments, the disease or disorder is alopecia (in embodiments, chemotherapy-induced alopecia). In embodiments, the disease or disorder is one where the patient is in need of enhancement of bone marrow mobilization in donors for stem cell transplant prior to retrieval, or where acceleration of bone marrow (especially neutrophil) engraftment in bone marrow transplant recipients.

[0013] As used herein, “treating” or “treatment” of any disease or disorder refers, inembodiments, to ameliorating a disease or disorder that exists in a subject. “Treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, “treating” or “treatment” includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying, preventing, or protecting against the onset of the disease or disorder. Further, as used herein, “treatment” may include preventing, delaying, or protecting against the recurrence of the disease, delaying or slowing the progression of the disease, alleviating a symptom of the disease state, increasing or improving the quality of life of the patient. In embodiments, the disease or disorder is neutropenia resulting from a cytotoxic therapy.

[0014] As used herein, the term “therapeutically effective amount” or “effective amount”refers to an amount of a substance of a composition comprising a substance that when administered to a subject is effective to alleviate neutropenia. For example, in an exemplary embodiment, the phrase “effective amount” is used interchangeably with “therapeutically - 14 - 1104747404\8\AMERICASeffective amount” or “therapeutically effective dose” and the like, and means an amount of a therapeutic agent that is effective to prevent, ameliorate, or protect against neutropenia or the progression of neutropenia to febrile neutropenia or result in amelioration of one or more symptoms or co-morbidities of neutropenia; to treat alopecia or chemistry-induced alopecia; or to enhance bone marrow mobilization in donors for stem cell transplant prior to retrieval, accelerate bone marrow (in embodiments neutrophil) engraftment in bone marrow transplant recipients, and / or to treat genetic neutropenias, (e.g. Severe Congenital Neutropenia (Kostmann Disease)).

[0015] Effective amounts of the compositions provided herein may vary according to factorssuch as the disease state, age, sex, weight of the animal, or human.

[0016] The term “pharmaceutical composition” as used herein shall mean a composition thatis made under conditions such that it is suitable for administration to humans, e.g., it is made under good manufacturing practice (GMP) conditions and contains pharmaceutically acceptable excipients. The pharmaceutical composition provided herein can be administrated to a subject in the context of alleviating neutropenia, and / or alleviating gastrointestinal toxicity. The pharmaceutical composition provided herein can also be administered to a subject in the context of alleviating alopecia (or chemotherapy-induced alopecia). In embodiments, a pharmaceutical composition comprises an active ingredient, e.g., arachidonic acid of high purity and / or one or more esters thereof of high purity, and a pharmaceutically acceptable excipient.

[0017] The term “medical food” as used herein refers to a formulation comprising atherapeutic agent e.g., arachidonic acid of high purity and / or one or more esters thereof of high purity, and / or an arachidonic acid glyceride composition, that is designed to be consumed under medical supervision and which is intended for the specific dietary management of a disease or condition, such as e.g., neutropenia. A “medical food” may be in the form of a complete nutritional product that is capable of being the sole source of nourishment for the subject in need thereof. Alternatively, a “medical food” may be in the form of a nutritional composition or a nutritional supplement that is intended to supplement the general diet of a subject.

[0018] A “medical food” may be formulated in any convenient form. For example a “medicalfood” may be in the form of a beverage, mayonnaise, salad dressing, margarine, low fat spread, dairy product, cheese spread, processed cheese, dairy dessert, flavored milk, cream, fermented milk product, cheese, butter, condensed milk product, ice cream mix, soya product, pasteurized liquid, egg, bakery product, confectionary product, confectionary bar, chocolate bar, high fat bar, liquid emulsion, spray-dried powder, freeze-dried powder, UHT pudding, pasteurized pudding, gel, jelly, yogurt, or a food with a fat-based or water-containing filling. - 15 - 1104747404\8\AMERICAS

[0019] In embodiments, a “medical food” is formulated for tube feeding. The term “tube feed”as used herein, refers to a product that is intended for introducing nutrients directly into the gastrointestinal tract of a subject by a feeding tube. A tube feed may be administered by, for example, a feeding tube placed through the nose of a subject (such as nasogastric, nasoduodenal, and nasojejunal tubes), or a feeding tube placed directly into the abdomen of a subject (such as gastrostomy, gastrojejunostomy, or jejunostomy feeding tube).

[0062] As used herein, “emulsifying agent” refers to a molecule with surface-activeproperties which causes immiscible oil and water phases to create dispersed colloidal system.

[0063] As used herein “co-solvent” refers to a solvent which is miscible in oil and water.

[0064] The term “pharmaceutically acceptable oil” as used herein a GMP grade oil that canbe consumed orally by humans.

[0065] The term “pharmaceutically acceptable wax” as used herein refers to lipid-basedexcipients with chemical structure that results in higher melting temperature (than room temperature) that can be consumed orally by humans.

[0066] As used herein “polysorbate 20,” refers to polyoxyethylene sorbitan monolauratecontaining 20 units of oxyethylene, which are hydrophilic, hygroscopic, nonionic surfactants that can be used as an emulsifying agent. In embodiments, the polysorbate 20 is Tween® 20. In other embodiments, the skilled person would recognize that Tween® 20 can be replaced with another polysorbate 20.

[0067] As used herein “polysorbate 80,” refers to polyoxyethylene sorbitan monooleatecontaining 20 units of oxyethylene, which are hydrophilic, hygroscopic, nonionic surfactants that can be used as an emulsifying agent. In embodiments, the polysorbate 80 is Tween® 80. In other embodiments, the skilled person would recognize that Tween® 80 can be replaced with another polysorbate 80.

[0068] As used herein, individual weight percentages are provided for various specificallyrecited ingredients in the pharmaceutical compositions disclosed herein, and these amounts are the relative amounts of each of the specifically recited components as a part of the total weight of the specifically recited components. In embodiments, even though the total amounts to 100%, additional components are not excluded from being present in the pharmaceutical composition. For example, the phrase “wherein the wt / wt% of the arachidonic acid of high purity and / or one or more esters thereof of high purity, the emulsifying agent, the optional co-solvent, the optional stabilizer, and the optional pharmaceutically acceptable oil total 100 wt / wt%” provides the relative of amounts of each of the specifically recited components as a part of the total weight of the specifically recited components, but the pharmaceutical composition may comprise additional - 16 - 1104747404\8\AMERICAScomponents. In embodiments, the phrase does not exclude additional components being present in the pharmaceutical composition.

[0069] As used herein “stabilizer” refers to one or more ingredients which helps maintain thechemical and physical properties of a compound or active ingredient. Inclusion of a stabilizer may provide a stable pharmaceutical composition as described herein.

[0070] By “stable pharmaceutical composition” is meant any pharmaceutical compositionhaving sufficient stability to have utility as a pharmaceutical product. In embodiments, a stable pharmaceutical composition has sufficient stability to allow storage, in embodiments, at a temperature between -20 °C and 40 °C (inclusive), in embodiments, about 2 °C to about 30 °C (inclusive), for a reasonable period of time, e.g., the shelf-life of the product. In embodiments, the pharmaceutical composition is stable when stored at about 15 ºC to about 25 ºC and about 60% relative humidity for a duration of time of at least one month, at least two months, at least 3 months, or at least six months. In embodiments, the pharmaceutical composition is stable when stored at about 25 ºC and about 60% relative humidity for a duration of time of at least one month, at least two months, or at least 3 months. In embodiments, the pharmaceutical composition is stable when stored at about 40 ºC and about 75% relative humidity for a duration of time of at least one month, at least two months, at least three months, or at least six months. In embodiments, the pharmaceutical composition is stable when stored at about 40 ºC and about 75% relative humidity for a duration of time of at least one month, at least two months, or at least three months. The shelf life of a product can be as short as one month but is typically six months or longer, in some embodiments, one year or longer, in some embodiments, twenty-four months or longer, and in some embodiments, thirty-six months or longer. The shelf-life or expiration can be that amount of time where the active ingredient degrades to a point below an acceptable purity level.

[0070] Unless defined otherwise, technical and scientific terms used herein have the samemeaning as commonly understood by a person of ordinary skill in the art. In particular, this disclosure utilizes routine techniques in the field of recombinant chemistry, genetics, immunology, and biochemistry. Basic texts disclosing the general terms in molecular biology and genetics include e.g., Lackie, Dictionary of Cell and Molecular Biology, Elsevier (5th ed. 2013). Basic texts disclosing methods in recombinant genetics and molecular biology include e.g., Sambrook et al, Molecular Cloning- A Laboratory Manual, Cold Spring Harbor Press 4th Edition (Cold Spring Harbor, N.Y.2012) and Current Protocols in Molecular Biology Volumes 1-3, John Wiley & Sons, Inc. (1994-1998) and Supplements 1-115 (1987-2016). Basic texts disclosing the general methods and terms in biochemistry include e.g., Lehninger Principles of Biochemistry sixth edition, David L. Nelson and Michael M. Cox eds. W.H. Freeman (2012). Basic texts - 17 - 1104747404\8\AMERICASdisclosing the general methods and terms immunology include Janeway's Immunobiology (Ninth Edition) by Kenneth M. Murphy and Casey Weaver (2017) Garland Science; Fundamental Immunology (Seventh Edition) by William E. Paul (2013) Lippincott, Williams and Wilkins.

[0071] In some embodiments, the pharmaceutical compositions provided herein may also helpalleviate certain co-morbidities of neutropenia such as anemia and gastrointestinal toxicity. In some embodiments, the gastrointestinal toxicity results in at least one symptom selected from mucositis and / or diarrhea. In some embodiments, the at least one symptom that is alleviated is selected from mucositis and / or diarrhea.

[0072] In some or any embodiments, the cytotoxic therapy is chemotherapy. In some or anyembodiments, the chemotherapy comprises an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a plant alkaloid, a topoisomerase inhibitor, and / or a mitotic inhibitor. In some or any embodiments, the alkylating agent is cyclophsophamide, the antimetabolite is 5-fluorouracil (5- FU), the anti-tumor antibiotic or plant alkaloid is doxorubicin, the topoisomerase inhibitor is irinotecan, and the mitotic inhibitor is paclitaxel. In some or any embodiments, the chemotherapy comprises a plant alkaloid. In one embodiment the plant alkaloid is doxorubicin.

[0078] A “pharmaceutical dosage form” as used herein means the pharmaceuticalcompositions disclosed herein being in a form of a capsule (usually referred to as single oral solid dosage form but includes a liquid filled capsule) or in a container and in an amount suitable for reconstitution and administration of one or more doses. The ultimate dosage form can be sterile, fluid and stable under the conditions of manufacture and storage. The prevention or inhibition of the growth of microorganisms can be accomplished by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0079] In some or any embodiments, administration of the arachidonic acid composition,arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is continued during the cytotoxic therapy. In some or any embodiments, administration of the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is continued subsequent to the cytotoxic therapy. In some or any embodiments, the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride - 18 - 1104747404\8\AMERICAScomposition is continued for at least one week, at least two weeks, at least three weeks, or at least four weeks subsequent to the cytotoxic therapy.

[0080] Neutropenia Resulting from Cytotoxic Therapies

[0081] Neutropenia is a major dose-limiting toxicity of chemotherapy that often requiresprolonged hospitalization and broad-spectrum antibiotic use, and occurrences of severe neutropenia or febrile neutropenia often trigger dose reductions and / or treatment delays in subsequent chemotherapy cycles and can compromise clinical outcome. Studies have shown that as many as 25% to 40% of treatment-naive patients develop febrile neutropenia with common chemotherapy regimens (Dale Drugs (2002) 62(Suppl 1):1–15), thereby increasing diagnostic and treatment costs and often leading to longer hospital stays. In addition, correlations have been reported between changes in neutrophil counts and quality of life, as measured by physical functioning, vitality, and mental health. Fortner et al. Support Care Cancer (2005) 13:522–528.

[0082] Febrile neutropenia (FN) in particular is associated with increased morbidity and anin‐hospital mortality rate around 10%, and despite significant advances in cancer care such as prophylactic use of myeloid growth factors FN remains to this day a major dose‐limiting event occurring during chemotherapy in patients with cancer. Aagaard et al., Cancer Med. (2020) May; 9(9): 3033–3042. Indeed, recent studies have found a 38% increased risk of all‐cause mortality after febrile neutropenia and a twofold higher risk of ICU admissions associated with organ failures related to severe infection. Id. Accordingly, more effective strategies for resolving neutropenia and avoiding and / or resolving febrile neutropenia are still sorely needed. The compositions and methods provided herein address these challenges.

[0083] Although the prophylactic use of myeloid growth factors in patients receivingcytotoxic therapies risk can reduce the severity and duration of febrile neutropenia, the reported mortality rates are still too high. Accordingly, the present disclosure also provides combination therapies with myeloid factors, wherein the one or more said myeloid growth factors is selected from the group consisting of granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF) and interleukin-3. In embodiments, the one or more myeloid growth factors is selected from filgrastim, filgrastim-sndz, tbo-filgrastim, pegfilgrastim, pegfilgrastim, lenograstim, argramostim, and molgramostim. Exemplary embodiments of these combination therapies include use with: 1. Prophylactic G-CSF for any cytotoxic therapy with 20% or greater frequency of Febrile Neutropenia 2. Prophylactic G-CSF for moderate risk (10-20%) cytotoxic regimens in populations with higher risk of FN (>65 yo, prior cancer therapies, poor renal function) - 19 - 1104747404\8\AMERICAS

[0084] The compositions and methods provided herein may also find advantageous use inenhancing bone marrow mobilization in donors for stem cell transplant prior to retrieval, for acceleration of bone marrow (especially neutrophil) engraftment in bone marrow transplant recipients, and for treatment of genetic neutropenias, e.g. Severe Congenital Neutropenia (Kostmann Disease).

[0085] While neutropenia is the most significant predisposing factor to infection, the impactof mucositis, i.e. damage to the mucosal barrier of the mouth and intestines, is a significant contributing factor and also a grave concern. Blijlevens et a., Clin. Microbiology and Infection, 7(s4):47-52 (2001). Infection can originate not just from exogenous sources but can also arise from the patient’s own endogenous microbial flora, particularly from those residing on the mucosal surfaces of the mouth and the gastrointestinal tract that are damaged with cytotoxic therapies. Id. The composition of the endogenous flora can also be altered by therapeutic interventions, particularly antibiotics, and changes in colonization can be followed by infection. Fainstein et al. J Infect Dis 1981; 144: 82–6. Accordingly, more effective strategies for resolving gastrointestinal toxicity co-morbidities of neutropenia such as mucositis and diarrhea are also sorely needed, and the pharmaceutical compositions provided herein can also address this unmet need.

[0086] Although not associated with morbidity or mortality, another damaging side effect ofcytotoxic therapies is hair loss that can also result from certain types of interventions. In this regard, Munkhbayar et al. report that arachidonic acid plays a role in promoting hair growth by increasing the expression of growth factors and enhancing follicle proliferation and survival. (Ann Dermatol 28(1):55-64 (2016)). Accordingly, the pharmaceutical compositions herein may also find advantageous use in treating chemotherapy-induced hair loss, and / or in treating alopecia in general.

[0001] The disclosure provides methods and compositions for alleviating neutropeniaresulting from a cytotoxic therapy. In embodiments, the methods and compositions provided herein may stabilize and / or increase a patient’s neutrophil count, and / or prevent or resolve febrile neutropenia.

[0002] In embodiments, the neutropenia results in at least one symptom selected from fever,fatigue, sore throat, swollen lymph nodes, mouth sores, pain, swelling and rash at an infection site, diarrhea, and burning with urination or other urinary symptoms such as urgency and / or frequency.

[0003] In embodiments, the at least one symptom that is alleviated is selected from selectedfrom fever, fatigue, sore throat, swollen lymph nodes, mouth sores, pain, swelling and rash at an - 20 - 1104747404\8\AMERICASinfection site, diarrhea, and burning with urination or other urinary symptoms such as urgency and / or frequency. In embodiments, one symptom is alleviated. In embodiments, two symptoms are alleviated. In embodiments, three symptoms are alleviated.

[0004] In some or any embodiments, the severity of the at least one symptom is alleviated,compared to a patient not pre-treated with an arachidonic acid composition. In some or any embodiments, the number of symptoms experienced by the patient is fewer (In some or any embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 fewer) compared to a patient not pre-treated with an arachidonic acid composition. In some or any embodiments, the number of times in a given period of time, that the patient experiences the at least one symptom is reduced compared to a patient not pre-treated with an arachidonic acid composition. Chemotherapy

[0005] Chemotherapy agents which can cause or be associated with neutropenia include, butare not limited to alkylating agents, antimetabolites, anti-tumor antibiotics, plant alkaloids, topoisomerase inhibitors / intercalators, and / or mitotic inhibitors. Alkylating agents

[0006] Alkylating agents are most active in the resting phase of the cell cycle. Alkylatingagents undergo strongly electrophilic chemical reactions through the formation of carbonium ion intermediates or of transition complexes with the target molecules. The cytotoxic effects of alkylating agents are directly related to the alkylation of components of DNA. Exemplary alkylating agents include, but are not limited to cyclophosphamide, mechlorethamine, melphalan, ifosfamide. Typical gastrointestinal toxicities include, but are not limited to nausea and vomiting abdominal pain and diarrhea. Antimetabolites

[0007] Antimetabolites such as e.g., folic acid, pyrimidine or purine analogues provideeffective chemotherapeutics. Antimetabolites have similar structures to naturally occurring molecules used in nucleic acid (DNA and RNA) synthesis. Generally, antimetabolites induce cell death during the S phase of cell growth and division because they primarily act upon cells undergoing synthesis by incorporating into RNA and DNA. They may also inhibit enzymes needed for nucleic acid production. Exemplary antimetabolites include but are not limited to 5- fluorouracil (5-FU). 5-Fluorouracil (5-FU) is an analogue of uracil that is metabolized to several cytotoxic forms. Gastrointestinal toxicities can be severe and life-threatening. - 21 - 1104747404\8\AMERICASAnti-tumor antibiotics

[0008] Antitumor antibiotics act by binding with DNA and preventing or inhibiting RNA(ribonucleic acid) synthesis. Exemplary antitumor antibiotics include, but are not limited to doxorubicin, mitoxantrone, and bleomycin. Plant alkaloids

[0009] Plant alkaloids are antitumor agents derived from plants. These drugs act specificallyby blocking cell division. Exemplary plant alkaloids include, but are not limited to actinomycin D, doxorubicin, and mitomycin. Topoisomerase inhibitors / intercalators

[0010] Intercalator-mediated cytotoxicity, can occur via numerous mechanisms includinge.g., by way of inhibition of DNA topoisomerase II and DNA replication. Gastrointestinal side effects include e.g., acute nausea and vomiting in and stomatitis. An exemplary topoisomerase inhibitor is irinotecan. Mitotic inhibitors

[0011] Mitotic inhibitors work by disrupting polymerization of microtubules. The principalmechanism through which the mitotic inhibitors stabilize microtubules is the strengthening of the lateral interactions between protofilaments. Exemplary mitotic inhibitors include, but are not limited to docetaxel and paclitaxel. Side effects of chemotherapy with mitotic inhibitors can be severe and include symptoms such as e.g., ischemic colitis which may result in severe complications including bowel necrosis, colonic perforation or typhlitis. Arachidonic acid

[0012] As discussed above, arachidonic acid is a carboxylic acid with a 20-carbon chain andfour cis-double bonds; the first double bond is located at the sixth carbon from the omega end, thus, arachidonic acid is an omega 6 fatty acid. The IUPAC name for arachidonic acid is (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoicacid. Arachidonic acid is a non-essential fatty acid. However, arachidonic acid is essential if a deficiency in linoleic acid exists or if an individual is unable to convert linoleic acid to arachidonic acid.

[0013] Arachidonic acid promotes the repair and growth of skeletal muscle tissue viaconversion to prostaglandin PGF2alpha during and following physical exercise. Accordingly, arachidonic acid is sometimes used as a bodybuilding supplement. - 22 - 1104747404\8\AMERICAS

[0014] Arachidonic acid is one of the most abundant fatty acids in the brain, and neurologicalhealth is reliant upon sufficient levels of arachidonic acid. Because of its abundance in the brain, arachidonic acid has been recommended as a dietary supplement to benefit individuals suffering from the early stages of Alzheimer's disease. However, its effectiveness as an Alzheimer’s treatment is unproven.

[0015] Arachidonic acid supplementation in daily doses of 1,000–1,500 mg for 50 days hasbeen well tolerated during several clinical studies, with no significant side effects reported. Thus, modest arachidonic acid supplementation of the diets of healthy adults appears to offer no toxicity or significant safety risk. The potential tumorigenic risk of higher doses, however, has been suggested in the prior art. See, e.g., D’ Angelo et al, Angelucci et al., Yarla et al., Wang et al., Finetti et al., Wen, et al, and Sakai et al., supra. Administration

[0016] Arachidonic acid composition, arachidonic acid of high purity and / or one or moreesters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition as disclosed herein can be administered by any method known in the art. For example, in some or any embodiments, the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is administered directly to the gastrointestinal tract. In other embodiments, the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is administered orally. In embodiments, the pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity is administered with food. In embodiments, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity is administered without food. Timing and Frequency of Administration

[0017] Arachidonic acid composition, arachidonic acid of high purity and / or one or moreesters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, and arachidonic acid glyceride composition may be administered a patient in need thereof in a therapeutically effective amount at any interval as long as the timing and amount are sufficient to alleviate at least one symptom gastrointestinal - 23 - 1104747404\8\AMERICAStoxicity. Typically, administration of the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is initiated prior to initiation of a cytotoxic therapy. In some or any embodiments, the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition administered at least once daily for at least 3 days prior to initiation of the cytotoxic therapy. In some or any embodiments, the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is administered twice daily for at least 3 days prior to initiation of the cytotoxic therapy. In some or any embodiments, the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is administered at least three days, at least four days, at least five days, at least six days, at least seven days, at least eight days, at least nine days, or at least ten days prior to initiating the cytotoxic therapy. In some or any embodiments, the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is administered at least one week, at least two weeks, at least three weeks, or at least four weeks prior to receiving the cytotoxic therapy.

[0018] In some or any embodiments, administration of the arachidonic acid composition,arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is continued during the cytotoxic therapy. In some or any embodiments, administration of the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is continued subsequent to the cytotoxic therapy. In some or any embodiments, administration of the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic - 24 - 1104747404\8\AMERICASacid glyceride composition is continued for at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, at least one week, at least two weeks, at least three weeks, or at least four weeks subsequent to the cytotoxic therapy. Dosage

[0019] The arachidonic acid composition, arachidonic acid of high purity and / or one or moreesters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition as disclosed herein is typically provided to a patient in need thereof in a therapeutically effective amount. A therapeutically effective amount of an arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition typically is at least about 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, at least about 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, at least about 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, at least about 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, at least about 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, at least about 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, at least about 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, at least about 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, or at least about 50 mg / kg per day. In some or any embodiments, the therapeutically effective amount of the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition at least about 10 mg / kg, at least about 15 mg / kg, at least about 20 mg / kg, at least about 25 mg / kg, at least about 30 mg / kg, at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, or at least about 50 mg / kg per day. Thus, in preferred embodiments, the therapeutically effective amount of the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is between about 25 mg / kg and about 100 mg / kg.

[0020] A pharmaceutical composition can comprise a unit dose formulation, where the unitdose is a dose sufficient to have a therapeutic effect. In the following embodiments, the weight refers to the effective amount of arachidonic acid and not the weight of, for example, of the arachidonic acid in its ester or glyceride forms. In embodiments, the total therapeutic daily dose of arachidonic acid is selected from about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, or about - 25 - 1104747404\8\AMERICAS7 g; or from about 2 g to about 7 g; or from about 3 g to about 6 g; or from about 4 g to about 6 g. In embodiments, the total daily dose is divided, for example, into multiple doses taken in a relatively short amount of time, for example, where the multiple doses are taken within about 1 minute to about 60 minutes of each other. In embodiments, each of the multiple doses that comprise the total daily dose is in the form of a capsule. In embodiments, each dose of the multiple doses that comprise the total daily dose is in the form of a capsule and the capsule contains a liquid pharmaceutical composition where the total weight of the liquid pharmaceutical composition is selected from about 400 mg to about 1200 mg; selected from about 500 mg to about 1100 mg; or selected from about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, and about 1150 mg. In embodiments, the total daily dose is provided as 3 to 8 capsules, 4 to 7 capsules, or 5 to 7 capsule.

[0021] In some or any embodiments, single or multiple doses can be administered. In some orany embodiments, the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is administered in single or multiple dosages at least once daily for at least 3 days prior to initiation of the cytotoxic therapy. In some or any embodiments, the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is administered twice daily for at least 3 days prior to initiation of the cytotoxic therapy. In some or any embodiments, the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is administered at least one week, at least two weeks, at least three weeks, or at least four weeks prior to receiving the cytotoxic therapy. In some or any embodiments, the arachidonic acid composition, arachidonic acid of high purity and / or one or more esters thereof of high purity, pharmaceutical composition comprising arachidonic acid of high purity and / or one or more esters thereof of high purity, or arachidonic acid glyceride composition is administered at least three days, at least four days, at least five days, at least six days, at least seven days, at least eight days, at least nine days, or at least ten days prior to initiating the cytotoxic therapy. - 26 - 1104747404\8\AMERICASFormulations Medical food formulations

[0022] Compositions of disclosed herein may take the form of medical foods. Typically, a“medical food” is meant a food which is formulated to be consumed or administered with or without the supervision of a physician and which is intended for a specific dietary management or condition with distinctive nutritional requirements. In some or any embodiments, a medical food is in the form of a complete nutritional product. A “complete nutritional product” is a product which is capable of being the sole source of nourishment for the subject and may be beneficial for individuals suffering from gastrointestinal toxicity.

[0023] In some or any embodiments, the “medical food” is a “nutritional supplement” whichis intended to supplement the general diet of a subject.Pharmaceutical compositions

[0024] The arachidonic acid compositions disclosed herein can be delivered to patient in needthereof using any method known in the art. Accordingly, the present disclosure also provides “pharmaceutically acceptable” or “physiologically acceptable” formulations. Such formulations can be administered in vivo to a subject in order to practice treatment methods.

[0025] As used herein, the terms “pharmaceutically acceptable” and “physiologicallyacceptable” refer to carriers, diluents, excipients and the like that can be administered to a subject, preferably without producing excessive adverse side-effects (e.g., nausea, abdominal pain, headaches, etc.). Such preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Liquid formulations include suspensions, solutions, syrups and elixirs. Liquid formulations may be prepared by the reconstitution of a solid.

[0026] Pharmaceutical formulations can be made from carriers, diluents, excipients, solvents,dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with administration to a subject. Such formulations can be contained in a tablet (coated or uncoated), capsule (hard or soft), microbead, emulsion, powder, granule, crystal, suspension, syrup or elixir. Supplementary active compounds and preservatives, among other additives, may also be present, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.

[0027] Excipients can include a salt, an isotonic agent, a serum protein, a buffer or other pH-controlling agent, an anti-oxidant, a thickener, an uncharged polymer, a preservative or a cryoprotectant. Excipients used in compositions of the disclosure may further include an isotonic agent and a buffer or other pH-controlling agent. These excipients may be added for the attainment - 27 - 1104747404\8\AMERICASof preferred ranges of pH (about 6.0-8.0) and osmolarity (about 50-400 mmol / L). Examples of suitable buffers are acetate, borate, carbonate, citrate, phosphate and sulfonated organic molecule buffer. Such buffers may be present in a composition in concentrations from 0.01 to 1.0% (w / v). An isotonic agent may be selected from any of those known in the art, e.g. mannitol, dextrose, glucose and sodium chloride, or other electrolytes. Preferably, the isotonic agent is glucose or sodium chloride. The isotonic agents may be used in amounts that impart to the composition the same or a similar osmotic pressure as that of the biological environment into which it is introduced. The concentration of isotonic agent in the composition will depend upon the nature of the particular isotonic agent used and may range from about 0.1 to 10%. When glucose is used, it is preferably used in a concentration of from 1 to 5% w / v, more particularly 5% w / v. When the isotonic agent is sodium chloride, it is preferably employed in amounts of up to 1% w / v, in particular 0.9% w / v.

[0028] The compositions of the disclosure may further contain a preservative. Examplespreservatives are polyhexamethylene-biguanidine, benzalkonium chloride, stabilized oxychloro complexes (such as those known as Purite®), phenylmercuric acetate, chlorobutanol, sorbic acid, chlorhexidine, benzyl alcohol, parabens, and thimerosal. Typically, such preservatives are present at concentrations from about 0.001 to 1.0%. Furthermore, the compositions of the disclosure may also contain a cryopreservative agent. Preferred cryopreservatives are glucose, sucrose, mannitol, lactose, trehalose, sorbitol, colloidal silicon dioxide, dextran of molecular weight preferable below 100,000 g / mol, glycerol, and polyethylene glycols of molecular weights below 100,000 g / mol or mixtures thereof. Most preferred are glucose, trehalose and polyethylene glycol. Typically, such cryopreservatives are present at concentrations from about 0.01 to 10%.

[0029] A pharmaceutical formulation can be formulated to be compatible with its intendedroute of administration. For example, for oral administration, a composition can be incorporated with excipients and used in the form of capsules, e.g., gelatin capsules, or coatings, e.g., enteric coatings (Eudragit® or Sureteric®). In embodiments, the pharmaceutical composition in the capsule is in liquid form. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included in oral formulations. The capsules, and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or other stearates; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or flavoring. - 28 - 1104747404\8\AMERICAS

[0030] Pharmaceutical compositions that are suitable for oral administration can be presentedas discrete dosage forms, such as, but are not limited to, caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 23rdedition (2020).

[0031] In embodiments, dosage forms for oral administration include, but are not limited tocaplets; capsules, such as soft elastic gelatin capsules; and liquid dosage forms, including dispersions, suspensions, solutions, and elixirs of solutions containing inert diluents and optionally containing wetting, sweetening, or flavoring agents.

[0032] Pharmaceutical solid dosage forms containing liquid formulations can be encapsulatedin two-piece hard capsules or soft gelatin capsules. For these capsule types, the outer capsule shell composition can be gelatin-based or contain another polymer including, but not limited to, hydroxypropylmethylcellulose, starch, pullulan and / or carrageenan. As required, plasticizers, solvent, coloring agents, opacifiers and stabilizers may be included in the capsule shell composition. The capsule shell can aid swallowing and mask taste, and the manufacturing process may include steps to prevent or protect against leakage of the liquid fill out of the capsule shell. In embodiments, the pharmaceutical composition in the capsule is in liquid form.

[0033] Typical oral dosage forms are prepared by combining the active ingredient(s) in anadmixture with at least one of the components of the formulation described herein, according to conventional pharmaceutical compounding techniques.

[0034] In embodiments, the capsule or oral liquid dosage forms can include water, glycols,oils, alcohols, flavoring agents, preservatives, and coloring agents.

[0035] In embodiments, additional components, e.g. one or more excipients, can be added tothe pharmaceutical compositions provided herein. As used herein, the term “excipient” means substances used to formulate active pharmaceutical ingredients (API) into pharmaceutical formulations; in an embodiment, an excipient does not lower or interfere with the primary therapeutic effect of the API. In embodiments, an excipient is therapeutically inert. The term “excipient” encompasses carriers, diluents, vehicles, solubilizers, stabilizers, bulking agents, and binders. Excipients can also be those substances present in a pharmaceutical formulation as an indirect or unintended result of the manufacturing process. In embodiments, excipients are approved for or considered to be safe for human and animal administration, e.g., generally regarded as safe (GRAS) substances. GRAS substances are listed by the Food and Drug administration in the Code of Federal Regulations (C.F.R.) at 21 C.F.R. §182 and 21 C.F.R. § 184, - 29 - 1104747404\8\AMERICASincorporated herein by reference. In embodiments, excipients include, but are not limited to, hexitols, including mannitol and the like.

[0036] Formulations can also include carriers to protect the composition against rapiddegradation or elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. For example, a time delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, may be employed.

[0037] Suppositories and other rectally administrable formulations (e.g., those administrableby enema) are also contemplated. Further regarding rectal delivery, see, for example, Song et al., Mucosal drug delivery: membranes, methodologies, and applications, Crit. Rev. Ther. Drug. Carrier Syst., 21:195-256, 2004; Wearley, Recent progress in protein and peptide delivery by noninvasive routes, Crit. Rev. Ther. Drug. Carrier Syst., 8:331-394, 1991.

[0038] Additional pharmaceutical formulations appropriate for administration are known inthe art and are applicable in the methods and compositions disclosed herein (see, e.g., Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing Co., Easton, Pa.; The Merck Index (1996) 12th ed., Merck Publishing Group, Whitehouse, N.J.; and Pharmaceutical Principles of Solid Dosage Forms, Technonic Publishing Co., Inc., Lancaster, Pa., (1993)).

[0039] Delivery systems useful in the context of embodiments of the disclosure may alsoinclude time-released, delayed release, and sustained release delivery systems such that the delivery of the compositions occurs prior to, and with sufficient time to cause, sensitization of the site to be treated. The composition can be used in conjunction with other therapeutic agents or therapies. Such systems can avoid repeated administrations of the composition, thereby increasing convenience to the subject and the physician, and may be particularly suitable for certain composition embodiments of the disclosure. SEDDS Pharmaceutical Compositions

[0120] Embodiment A: Provided is a pharmaceutical composition, comprising arachidonicacid of high purity and / or one or more esters thereof of high purity; and one or more pharmaceutically acceptable excipients independently selected from the group consisting of an emulsifying agent, a pharmaceutically acceptable oil or pharmaceutically acceptable wax, and a co-solvent; and additionally comprising an optional stabilizer.

[0121] Embodiment A1a: In an embodiment of Embodiment A, provided is a pharmaceuticalcomposition comprising arachidonic acid of high purity and / or one or more esters thereof of high - 30 - 1104747404\8\AMERICASpurity; one or more emulsifying agents; one or more optional co-solvents; one or more optional stabilizers; and one or more optional pharmaceutically acceptable oils.

[0122] Embodiment A1b: In an embodiment of Embodiment A, provided is a pharmaceuticalcomposition a) comprising arachidonic acid of high purity and / or one or more esters thereof of highpurity; an emulsifying agent; and an optional stabilizer; wherein one or at least one emulsifying agent is selected from the group consisting of polyglyceryl-3 dioleate, sorbitan monopalmitate 40, sorbitan monopalmitate 60, propylene glycol caprylate, a polysorbate 20, D-α-tocopherol polyethylene glycol 1000 succinate, a phosphatidyl choline, and a lyso-phosphatidyl choline; or b) comprising arachidonic acid of high purity and / or one or more esters thereof of highpurity; a pharmaceutically acceptable oil or pharmaceutically acceptable wax; and an optional stabilizer; or c) comprising arachidonic acid of high purity and / or one or more esters thereof of highpurity; a co-solvent; and an optional stabilizer; and wherein for b) and c), the pharmaceutical composition does not comprise an emulsifying agent.

[0123] Embodiment A1c. In an embodiment of any one of embodiment A and A1a, providedis a pharmaceutical composition comprising: a) about 70 wt / wt% to about 98.5 wt / wt% of arachidonic acid of high purity and / orone or more esters thereof of high purity; in an embodiment, about 90 wt / wt% to about 99.5 wt / wt%; b) about 0.5 wt / wt% to about 20 wt / wt% in total of one or more emulsifying agents;in embodiments, about 0.5 wt / wt% to about 10 wt / wt%; c) one or more optional co-solvents, wherein when present is present in about 0.5wt / wt% to about 10 wt / wt% in total; in an embodiment, about 0.5 wt / wt% to about 10 wt / wt%; d) one or more optional stabilizers, wherein when present is present in about 0.001wt / wt% to about 1 wt / wt% in total; and e) one or more optional pharmaceutically acceptable oils, when present is present inabout 0.5 wt / wt% to about 20 wt / wt% in total; in an embodiment, about 0.5 wt / wt% to about 10 wt / wt%; wherein the wt / wt% of the arachidonic acid of high purity and / or one or more esters thereof of high purity, the emulsifying agent(s), the optional co-solvent(s), the optional stabilizer(s), and the optional pharmaceutically acceptable oil(s) total 100 wt / wt%. - 31 - 1104747404\8\AMERICAS

[0124] Embodiment A1d: In an embodiment of embodiment A or A1b, provided is apharmaceutical composition comprising: 1) about 90 wt / wt% to about 99.5 wt / wt% of arachidonic acid of high purity and / or oneor more esters thereof of high purity; and a) about 0.5 wt / wt% to about 10 wt / wt% in total of one or more emulsifyingagents; or b) about 0.5 wt / wt% to about 10 wt / wt% in total of one or more pharmaceuticallyacceptable oils; or c) about 0.5 wt / wt% to about 10 wt / wt% in total of one or more co-solvents;and 2) an optional stabilizer, wherein when present is present in about 0.001 wt / wt% to about1 wt / wt%; and wherein the wt / wt% of 1), a), and 2) total 100 wt / wt%; the wt / wt% of 1), b), and 2) total 100 wt / wt%; and the wt / wt% of 1), c), and 2) total 100 wt / wt%.

[0125] Embodiment A1e: In an embodiment of any one of embodiments A to A1c,provided is a pharmaceutical composition, comprising arachidonic acid of high purity and / or one or more esters thereof of high purity; one or more emulsifying agents; and one or more optional stabilizers; and optionally wherein the pharmaceutical composition does not comprise a pharmaceutically acceptable oil or pharmaceutically acceptable wax, and additionally optionally wherein the pharmaceutical composition does not comprise a co-solvent.

[0126] Embodiment A2-1: In an embodiment of any one of Embodiments A, A1a, and A1cto A1e, the emulsifying agent(s), when present, contains a fatty acid chain in its structure. In embodiments, the emulsifying agent(s) containing a fatty acid chain in its structure are independently selected from the group consisting of polyglyceryl-3 dioleate, sorbitan monopalmitate 40, sorbitan monopalmitate 60, propylene glycol caprylate, a polysorbate 20, D- α-tocopherol polyethylene glycol 1000 succinate, a phosphatidyl choline, a lyso-phosphatidyl choline, polysorbate 80, caprylocaproyl polyoxyl-8 glycerides, oleoyl polyoxyl-6 glycerides, mono-, di- and triglyceride esters of fatty acids (C8to C18), and lauroyl polyoxyl-32 glycerides.

[0127] Embodiment A2-2: In an embodiment of any one of embodiments A to A1e, one ormore (in embodiments, one or two) of the emulsifying agents are independently selected from the group consisting of a polysorbate 20; polysorbate 80; PEG-40 hydrogenated, ethoxylated castor oil; lauroyl polyoxyl-32 glycerides; caprylocaproyl polyoxyl-8 glycerides; oleoyl polyoxyl-6 glycerides; mono-, di- and triglyceride esters of fatty acids (C8 to C18), the triester fraction being predominant (“hard fat”); polyglyceryl-3 dioleate; sorbitan monopalmitate 40; sorbitan - 32 - 1104747404\8\AMERICASmonostearate 60; propylene glycol monocaprylate NF [may also be labeled as propylene glycol monocaprylate (type II) NF until December 1, 2026]; a-tocopherol poly-ethylene glycol succinate; phosphatidyl choline; and lyso-phosphatidyl choline.

[0128] Embodiment A2: In an embodiment of embodiment A1a or A1c, the emulsifyingagent is selected from a polysorbate 80; PEG-40 hydrogenated, ethoxylated castor oil; lauroyl polyoxyl-32 glycerides; caprylocaproyl polyoxyl-8 glycerides; oleoyl polyoxyl-6 glycerides; and mono-, di- and triglyceride esters of fatty acids (C8 to C18), the triester fraction being predominant (“hard fat”).

[0129] Embodiment A2a-1: In an embodiment of any one of embodiments A to A2-2, oneor more (in embodiments, one or two) of the emulsifying agents is a polysorbate 20. In embodiments, the polysorbate 20 is Tween® 20.

[0130] Embodiment A2a: In an embodiment of any one of embodiments A to A2, one ormore (in embodiments, one or two) of the emulsifying agents is a polysorbate 80. In embodiments, the polysorbate 80 is Tween80®.

[0131] Embodiment A2b: In an embodiment of any one of embodiments A to A2, one ormore (in embodiments, one or two) of the emulsifying agents is a PEG-40 hydrogenated, ethoxylated castor oil. In embodiments, the PEG-40 hydrogenated castor oil is Cremophor® RH40.

[0132] Embodiment A2c: In an embodiment of any one of embodiments A to A2, one ormore (in embodiments, one or two) of the emulsifying agents is lauroyl polyoxyl-32 glycerides. In embodiments, the lauroyl polyoxyl-32 glycerides is Gelucire® 44 / 14.

[0133] Embodiment A2d: In an embodiment of any one of embodiments A to A2, one ormore (in embodiments, one or two) of the emulsifying agents is caprylocaproyl polyoxyl-8 glycerides. In embodiments, the caprylocaproyl polyoxyl-8 glycerides is Labrasol®.

[0134] Embodiment A2e: In an embodiment of any one of embodiments A to A2, one ormore (in embodiments, one or two) of the emulsifying agents is oleoyl polyoxyl-6 glycerides. In embodiments, the oleoyl polyoxyl-6 glycerides is Labrafil® M1944 CS.

[0135] Embodiment A2f: In an embodiment of any one of embodiments A to A2, one ormore (in embodiments, one or two) of the emulsifying agents is mono-, di- and triglyceride esters of fatty acids (C8 to C18), the triester fraction being predominant. In embodiments, the emulsifying agent is Gelucire® 43 / 01.

[0136] Embodiment A2g: In an embodiment of any one of embodiments A to A2-2, one ormore (in embodiments, one or two) of the emulsifying agents is polyglyceryl-3 dioleate. In embodiments, the emulsifying agent is plurol oleique. - 33 - 1104747404\8\AMERICAS

[0137] Embodiment A2h: In an embodiment of any one of embodiments A to A2-2, one ormore (in embodiments, one or two) of the emulsifying agents is sorbitan monopalmitate 40. In embodiments, the emulsifying agent is Span™ 40.

[0138] Embodiment A2i: In an embodiment of any one of embodiments A to A2-2, one ormore (in embodiments, one or two) of the emulsifying agents is sorbitan monostearate 60. In embodiments, the emulsifying agent is Span™ 60.

[0139] Embodiment A2j: In an embodiment of any one of embodiments A to A2-2, one ormore (in embodiments, one or two) of the emulsifying agents is propylene glycol monocaprylate NF [may also be labeled as propylene glycol monocaprylate (type II) NF until December 1, 2026]. In embodiments, the emulsifying agent is Capryol® 90.

[0140] Embodiment A2k: In an embodiment of any one of embodiments A to A2-2, one ormore (in embodiments, one or two) of the emulsifying agents is a-tocopherol poly-ethylene glycol succinate (also known as Vit E TPGS or Vitamin E TPGS).

[0141] Embodiment A2m: In an embodiment of any one of embodiments A to A2-2, one ormore (in embodiments, one or two) of the emulsifying agents is phosphatidyl choline.

[0142] Embodiment A2n: In an embodiment of any one of embodiments A to A2-2, one ormore (in embodiments, one or two) of the emulsifying agents is lyso-phosphatidyl choline.

[0143] Embodiment A2p: In an embodiment of any one of embodiments A to A2e-8, the oneor more (in embodiments, one or two) of the emulsifying agents are present in a total amount selected from about 5% to about 10% or selected from about 2% to about 6% or selected from about 2.5% and about 5%.

[0144] Embodiment A3-1: In an embodiment of any one of embodiments A, A1b, and A1d,provided is a pharmaceutical composition, comprising arachidonic acid of high purity and / or one or more esters thereof of high purity; one or more co-solvents; and one or more optional stabilizera; wherein the pharmaceutical composition does not comprise an emulsifying agent and additionally optionally wherein the pharmaceutical composition does not comprise a pharmaceutically acceptable oil or pharmaceutically acceptable wax.

[0145] Embodiment A3: In an embodiment of any one of embodiments A to A3-1, at leastone or exactly one of the optional co-solvents, when present, is selected from a polyethylene glycol (in embodiments PEG400) or a propylene glycol.

[0146] Embodiment A3a: In an embodiment of any one of embodiments A to A3-1, the co-solvent(s), when present, is present in a total amount selected from about 5% to about 10% or selected from about 2% to about 6% or selected from about 2.5% and about 5%. - 34 - 1104747404\8\AMERICAS

[0147] Embodiment A3b: In an embodiment of any one of embodiments A to A3a, whereina co-solvent(s) is present and optionally wherein one co-solvent is present.

[0148] Embodiment A4: In an embodiment of any one of embodiments A to A3b, at leastone or exactly one of the optional stabilizer(s), when present, is selected from is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and d-alpha-tocopherol.

[0149] Embodiment A4a: In an embodiment of any one of embodiments A to A4, thestabilizer(s), when present, is present in a total amount selected from about 0.01% to about 0.025% or selected from about 0.01% to about 0.1% or selected from a non-zero amount of 0.1% or less.

[0150] Embodiment A4b: In an embodiment of any one of embodiments A to A4, astabilizer(s) is present and optionally one stabilizer is present.

[0151] Embodiment A5-1: In an embodiment of any one of embodiments A, A1b, and A1d,provided is a pharmaceutical composition, comprising arachidonic acid of high purity and / or one or more esters thereof of high purity; one or more pharmaceutically acceptable oils or pharmaceutically acceptable waxes; and one or more optional stabilizers; wherein the pharmaceutical composition does not comprise an emulsifying agent and additionally optionally wherein the pharmaceutical composition does not comprise a co-solvent.

[0152] Embodiment A5: In an embodiment of any one of embodiments A to A4b, at leastone or exactly one of the pharmaceutically acceptable oil(s), when present, is selected from one or more fatty acid glycerides (including mono-, di or tri-glycerides), and / or one or more free fatty acids (including oleic acid).

[0153] Embodiment A5a-1: In an embodiment of any one of embodiments A to A5, at leastone or exactly one of the pharmaceutically acceptable oil(s) or pharmaceutically acceptable wax(es), as applicable, when present, is selected from medium-chain monoglycerides (e.g. glyceryl caprylate, glyceryl caprate), or long-chain monoglycerides (e.g. glyceryl monooleate (glyceryl monooleate (Type 40) or PeceolTM) and glyceryl monostearate).

[0154] Embodiment A5b-1: In an embodiment of any one of embodiments A to A5, at leastone or exactly one of the pharmaceutically acceptable oil(s) or pharmaceutically acceptable wax(es), as applicable, when present, is selected from medium-chain diglycerides (e.g. glyceryl dilaurate), or long-chain diglycerides (e.g. glyceryl dioleate and glyceryl distearate).

[0155] Embodiment A5b: In an embodiment of any one of embodiments Ala, A1c, A2,A2a to A2f, and A3 to A4a the pharmaceutically acceptable oil, when present, is selected from - 35 - 1104747404\8\AMERICASmedium-chain diglycerides (e.g. glyceryl dilaurate), or long-chain diglycerides (e.g. glyceryl dioleate).

[0156] Embodiment A5c: In an embodiment of any one of embodiments A to A5, at leastone or exactly one of the pharmaceutically acceptable oil(s), when present, is selected from medium-chain triglycerides [e.g. triglyceride ester of saturated coconut / palm kernel oil derived caprylic and capric fatty acids and plant derived glycerol (Miglyol® 812), caprylic / capric triglyceride (Captex® 355), medium-chain triglycerides of caprylic (C8) and capric (C10) acids (Labrafac™ Lipophile WL 1349), propylene glycol dicaprolate / dicaprate (Labrafac™ PG) glyceryl mono and dicaprylocaprate (Labrafac™ MC60); and mixed decanoyl and octanoyl glycerides, (Labrafac™ N MB)]; and long-chain triglycerides (e.g. soybean oil, olive oil, and corn oil).

[0157] Embodiment A5d: In an embodiment of any one of embodiments A to A5, at leastone or exactly one of the pharmaceutically acceptable oil(s) or pharmaceutically acceptable wax(es), as applicable, when present, is selected from free fatty acids, e.g. oleic acid, linoleic acid, linolenic acid and stearic acid.

[0158] Embodiment A5e: In an embodiment of any one of embodiments A to A5d, thepharmaceutically acceptable oil(s) or pharmaceutically acceptable wax(es) when present, is present in a total amount of about 5% to about 10% or selected from about 2% to about 6% or selected from about 2.5% and about 5%.

[0159] Embodiment A5f: In an embodiment of any one of embodiments A to A5e, apharmaceutically acceptable oil or pharmaceutically acceptable wax is present and optionally one pharmaceutically acceptable oil or pharmaceutically acceptable wax is present.

[0160] Embodiment A6: In an embodiment of any one of embodiments A to A5e, thearachidonic acid of high purity and / or esters thereof of high purity is arachidonic acid of high purity.

[0161] Embodiment A7: In an embodiment of any one of embodiments A to A5e, thearachidonic acid of high purity and / or one or more esters thereof of high purity is a combination of arachidonic acid of high purity and one or more esters of arachidonic acid of high purity. In embodiments, the one or more arachidonic acid esters of high purity is a combination of arachidonic acid of high purity and arachidonic acid ethyl ester of high purity.

[0162] Embodiment A8: In an embodiment of any one of embodiments A to A5e, thearachidonic acid of high purity and / or one or more esters thereof of high purity is arachidonic acid of high purity or one or more esters of arachidonic acid of high purity. In embodiments, the one - 36 - 1104747404\8\AMERICASor more arachidonic acid esters of high purity is arachidonic acid of high purity or arachidonic acid ethyl ester of high purity.

[0163] Embodiment A9: In an embodiment of any one of embodiments A to A5e, thearachidonic acid of high purity and / or one or more esters thereof of high purity is one or more esters of arachidonic acid of high purity. In embodiments, the one or more arachidonic acid esters of high purity is arachidonic acid ethyl ester of high purity.

[0164] Embodiment A10: In an embodiment of any one of embodiments A to A8, thearachidonic acid of high purity has a purity of about 80% or greater, about 85% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 80% to about 90%, about 80% to about 95%, about 85% to about 95%, about 85% to about 90%, or about 90% to about 95% as measured by GC.

[0165] Embodiment A11: In an embodiment of any one of embodiments A to A5e and A7to A10, the one or more arachidonic acid ester of high purity has a purity of about 80% or greater, about 85% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 98.5% or greater, about 80% to about 90%, about 80% to about 95%, about 85% to about 95%, about 85% to about 90%, or about 90% to about 95% as measured by GC.

[0166] Embodiment A12: In an embodiment of any one of embodiments A to A11, thearachidonic acid of high purity and / or one or more esters thereof is in an amount of about 75 wt / wt%, about 80 wt / wt%, about 81 wt / wt%, about 82 wt / wt%, about 83 wt / wt%, about 84 wt / wt%, about 85 wt / wt%, about 86 wt / wt%, about 87 wt / wt%, about 88 wt / wt%, about 89 wt / wt%, or about 90 wt / wt%. In an embodiment of any one of embodiments A to A11, the arachidonic acid of high purity and / or one or more esters thereof is in an amount from about 80 wt / wt% to about 85 wt / wt%, from about 85 wt / wt% to about 90 wt / wt%, or from about 80 wt / wt% to about 90 wt / wt%.

[0167] Embodiment A13: In an embodiment of any one of embodiments A to A12, thepharmaceutical composition is an oral pharmaceutical composition.

[0168] Embodiment A13a: In an embodiment of any one of embodiments A to A13, thepharmaceutical composition is in a capsule. In embodiments, the pharmaceutical composition in the capsule is in liquid form.

[0169] Embodiment A13b: In an embodiment of any one of embodiments A to A13a, thepharmaceutical composition is in a hard gelatin capsule. - 37 - 1104747404\8\AMERICAS

[0170] Embodiment A13c: In an embodiment of any one of embodiments A to A13a, thepharmaceutical composition is in a soft gel capsule.

[0171] Embodiment A13d: In an embodiment of any one of embodiments A to A13, thepharmaceutical composition is a liquid. In embodiments, the liquid pharmaceutical composition is in a capsule.

[0172] Embodiment A13e: In an embodiment of any one of embodiments A to A13 andA13d, the pharmaceutical composition is a liquid suitable for administration by a feeding tube.

[0173] Embodiment A13f: In an embodiment of any one of embodiments A to A13, thepharmaceutical composition is in a gummy.

[0174] Embodiment A13g: In an embodiment of any one of embodiments A to A13, thepharmaceutical composition is in granular form. Additional Embodiments

[0175] Embodiment B1. Provided is a pharmaceutical composition comprising arachidonicacid and / or one or more esters thereof of high purity; an emulsifying agent; an optional co-solvent; an optional stabilizer; and an optional pharmaceutically acceptable oil.

[0176] Embodiment B2. Provided is the pharmaceutical composition of embodiment B1,comprising a) about 70 wt / wt% to about 98.5 wt / wt% of arachidonic acid and / or one or more estersthereof of high purity; b) about 0.5 wt / wt% to about 20 wt / wt% of an emulsifying agent;c) an optional co-solvent, wherein about 0.5 wt / wt% to about 10 wt / wt% of a co-solvent; d) an optional stabilizer, wherein about 0.001 wt / wt% to about 1 wt / wt% of astabilizer; and e) an optional pharmaceutically acceptable oil, when present is present in about 0.5wt / wt% to about 20 wt / wt%; wherein the wt / wt% of the arachidonic acid and / or one or more esters thereof of high purity, the emulsifying agent, the optional co-solvent, the optional stabilizer, and the optional pharmaceutically acceptable oil total 100 wt / wt%.

[0177] Embodiment B3. Provided is the pharmaceutical composition of embodiments B1 orB2, wherein the emulsifying agent is selected from a polysorbate 80; PEG-40 hydrogenated, ethoxylated castor oil; lauroyl polyoxyl-32 glycerides; caprylocaproyl polyoxyl-8 glycerides; - 38 - 1104747404\8\AMERICAScaprylocaproyl polyoxyl-8 glycerides; oleoyl polyoxyl-6 glycerides; and mono-, di- and triglyceride esters of fatty acids (C8 to C18), the triester fraction being predominant (“hard fat”);.

[0178] Embodiment B4. Provided is the pharmaceutical composition of any one ofembodiments B1 to B3, wherein the emulsifying agent is a polysorbate 80.

[0179] Embodiment B5. Provided is the pharmaceutical composition of any one ofembodiments B1 to B3, wherein the emulsifying agent is a PEG-40 hydrogenated, ethoxylated castor oil.

[0180] Embodiment B6. Provided is the pharmaceutical composition of any one ofembodiments B1 to B3, wherein the emulsifying agent is lauroyl polyoxyl-32 glycerides.

[0181] Embodiment B7. Provided is the pharmaceutical composition of any one ofembodiments B1 to B3, wherein the emulsifying agent is caprylocaproyl polyoxyl-8 glycerides.

[0182] Embodiment B7a. Provided is the pharmaceutical composition of any one ofembodiments B1 to B3, wherein the emulsifying agent is oleoyl polyoxyl-6 glycerides.

[0183] Embodiment B7b. Provided is the pharmaceutical composition of any one ofembodiments B1 to B3, wherein the emulsifying agent is mono-, di- and triglyceride esters of fatty acids (C8 to C18), the triester fraction being predominant.

[0184] Embodiment B8. Provided is the pharmaceutical composition of any one ofembodiments B1 to B7b, wherein the emulsifying agent is present in an amount of about 5% to about 10%.

[0185] Embodiment B9. Provided is the pharmaceutical composition of any one ofembodiments B1 to B8, wherein the co-solvent, when present, is selected from a polyethylene glycol (in embodiments PEG400) or a propylene glycol.

[0186] Embodiment B10. Provided is the pharmaceutical composition of any one ofembodiments B1 to B9, wherein the co-solvent, when present, is present in an amount of about 5% to about 10%.

[0187] Embodiment B11. Provided is the pharmaceutical composition of any one ofembodiments B1 to B10, wherein a co-solvent is present.

[0188] Embodiment B12. Provided is the pharmaceutical composition of any one ofembodiments B1 to B11, wherein the optional stabilizer, when present, is selected from is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and d-alpha-tocopherol.

[0189] Embodiment B13. Provided is the pharmaceutical composition of any one ofembodiments B1 to B12, wherein the stabilizer, when present, is present in an amount of about 0.01 to about 0.025%. - 39 - 1104747404\8\AMERICAS

[0190] Embodiment B14. Provided is the pharmaceutical composition of any one ofembodiments B1 to B13, wherein a stabilizer is present.

[0191] Embodiment B15. Provided is the pharmaceutical composition of any one ofembodiments B1 to B14, wherein the pharmaceutically acceptable oil, when present, is selected from one or more fatty acid glycerides (including mono-, di or tri-glycerides), and / or one or more free fatty acids.

[0192] Embodiment B16. Provided is the pharmaceutical composition of any one ofembodiments B1 to B15, wherein the pharmaceutically acceptable oil, when present, is present in an amount of about 5% to about 10%.

[0193] Embodiment B17. Provided is the pharmaceutical composition of any one ofembodiments B1 to B16, wherein the arachidonic acid and / or esters thereof of high purity is arachidonic acid of high purity.

[0194] Embodiment B18. Provided is the pharmaceutical composition of any one ofembodiments B1 to B17, wherein the arachidonic acid and / or one or more esters thereof of high purity is a combination of arachidonic acid and one or more esters of arachidonic acid of high purity; preferably wherein the one or more arachidonic acid esters of high purity is arachidonic acid ethyl ester of high purity.

[0195] Embodiment B19. Provided is the pharmaceutical composition of any one ofembodiments B1 to B18, wherein the arachidonic acid and / or one or more esters thereof of high purity is arachidonic acid or one or more esters of arachidonic acid of high purity; preferably wherein the one or more arachidonic acid esters of high purity is arachidonic acid ethyl ester of high purity.

[0196] Embodiment B20. Provided is the pharmaceutical composition of any one ofembodiments B1 to B19, wherein the arachidonic acid and / or one or more esters thereof of high purity is one or more esters of arachidonic acid of high purity; preferably wherein at least one is arachidonic acid ethyl ester of high purity.

[0197] Embodiment B21. Provided is the pharmaceutical composition of any one ofembodiments B1 to B20, wherein the arachidonic acid of high purity has a purity of about 80% or greater, about 85% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, or about 99% or greater as measured by GC.

[0198] Embodiment B22. Provided is the pharmaceutical composition of any one ofembodiments B1 to B21, wherein the one or more arachidonic acid ester of high purity has a purity of about 80% or greater, about 85% or greater, about 90% or greater, about 91% or greater, about - 40 - 1104747404\8\AMERICAS92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, or about 98.5% or greater; wherein some embodiments the purity is measured by GC.

[0199] Embodiment B23. Provided is the pharmaceutical composition of any one ofembodiments B1 to B22, wherein the arachidonic acid and / or one or more esters thereof of high purity is in an amount of about 75 wt / wt%, about 80 wt / wt%, about 81 wt / wt%, about 82 wt / wt%, about 83 wt / wt%, about 84 wt / wt%, about 85 wt / wt%, about 86 wt / wt%, about 87 wt / wt%, about 88 wt / wt%, about 89 wt / wt%, or about 90 wt / wt%; or from about 80 wt / wt% to about 85 wt / wt%, from about 85 wt / wt% to about 90 wt / wt%, or from about 80 wt / wt% to about 90 wt / wt%.

[0200] Embodiment B24. Provided is the pharmaceutical composition of any one ofembodiments B1 to B23, wherein the pharmaceutical composition is an oral pharmaceutical composition.

[0201] Embodiment B25. Provided is the pharmaceutical composition of any one ofembodiments B1 to B24, wherein the pharmaceutical composition is in a capsule, preferably in a hard gelatin capsule.

[0202] Embodiment B26. Provided is the pharmaceutical composition of any one of claims 1to 24, wherein the pharmaceutical composition is a liquid.

[0203] Embodiment B27. Provided is a method for alleviating neutropenia resulting from acytotoxic therapy in a cancer patient, the method comprising: administering a therapeutically effective amount of an arachidonic acid composition to the patient at least 3 days prior to initiation of the cytotoxic therapy.

[0204] Embodiment B28. Provided is the method of embodiment B27, further comprisingadministering one or more myeloid growth factors to said patient; preferably wherein the one or more said myeloid growth factors is selected from the group consisting of granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G- CSF), macrophage colony-stimulating factor (M-CSF) and interleukin-3.

[0205] Embodiment B29. Provided is the method of embodiment B28, wherein the one ormore myeloid growth factors is selected from filgrastim, filgrastim-sndz, tbo-filgrastim, pegfilgrastim, pegfilgrastim, lenograstim, argramostim, and molgramostim.

[0206] Embodiment B30. Provided is the method of any one of embodiments B27 to B29,wherein the arachidonic acid composition is or comprises arachidonic acid and / or one or more esters thereof of high purity, and preferably wherein the arachidonic acid and / or one or more esters thereof of high purity is arachidonic acid and / or an ethyl ester thereof of high purity. - 41 - 1104747404\8\AMERICAS

[0207] Embodiment B31. Provided is the method of embodiment B30, wherein arachidonicacid and / or one or more esters thereof of high purity is provided as a pharmaceutical composition of any one of claims 1 to 26.

[0208] Embodiment B31a. Provided is the method of any one of embodiments B27 to B29,wherein the arachidonic acid composition is or comprises an arachidonic acid glyceride composition.

[0209] Embodiment B32. Provided is the method of any one of embodiments B27 to B31a,wherein the cytotoxic therapy is chemotherapy.

[0210] Embodiment B33. Provided is the method of embodiment B32, wherein thechemotherapy comprises an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a plant alkaloid, a topoisomerase inhibitor, and / or a mitotic inhibitor.

[0211] Embodiment B34. Provided is the method of embodiment B33, wherein the alkylatingagent is cyclophsophamide, the antimetabolite is 5-fluorouracil (5-FU), the anti-tumor antibiotic or plant alkaloid is doxorubicin, the topoisomerase inhibitor is irinotecan, and the mitotic inhibitor is paclitaxel.

[0212] Embodiment B35. Provided is the method of embodiment B33, wherein thechemotherapy comprises a plant alkaloid; preferably wherein the plant alkaloid is doxorubicin.

[0213] Embodiment B36. Provided is the method of any one of embodiments B27 to B35,wherein the arachidonic acid composition is administered at least once daily or exactly once daily for at least 3 days prior to initiation of the cytotoxic therapy.

[0214] Embodiment B37. Provided is the method of any one of embodiments B27 to B35,wherein the arachidonic acid composition is administered twice daily for at least 3 days prior to initiation of the cytotoxic therapy.

[0215] Embodiment B38. Provided is the method of any one of embodiments B27 to B35,wherein the arachidonic acid composition is administered at least one week, at least two weeks, at least three weeks, or at least four weeks prior to receiving the cytotoxic therapy.

[0216] Embodiment B39. Provided is the method of any one of embodiments B27 to B35,wherein the arachidonic acid composition is administered at least three days, at least four days, at least five days, at least six days, at least seven days, at least eight days, at least nine days, or at least ten days prior to initiating the cytotoxic therapy.

[0217] Embodiment B40. Provided is the method of any one of embodiments B27 to B39,wherein administration of the arachidonic acid composition is continued during the cytotoxic therapy. - 42 - 1104747404\8\AMERICAS

[0218] Embodiment B41. Provided is the method of any one of embodiments B27 to B40,wherein administration of the arachidonic acid composition is continued subsequent to the cytotoxic therapy.

[0219] Embodiment B42. Provided is the method of embodiment B41, wherein administrationof the arachidonic acid composition is continued for at least one week, at least two weeks, at least three weeks, or at least four weeks subsequent to the cytotoxic therapy.

[0220] Embodiment B43. Provided is the method of any one of embodiments B27 to B42,wherein the therapeutically effective amount of the arachidonic acid composition is at least about 10 mg / kg, at least about 15 mg / kg, at least about 20 mg / kg, at least about 25 mg / kg, at least about 30 mg / kg, at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, or at least about 50 mg / kg per day; preferably wherein the arachidonic acid composition comprises 25% to 100% by weight of arachidonic acid and / or ester(s) thereof, based on the total weight of the arachidonic acid composition.

[0221] Embodiment B44. Provided is the method of any of embodiments B27 to B43, whereinthe therapeutically effective amount of the arachidonic acid composition is between about 25 mg / kg and about 100 mg / kg, inclusive; preferably wherein the arachidonic acid composition comprises 25% to 100% by weight of arachidonic acid and / or ester(s) thereof, based on the total weight of the arachidonic acid composition.

[0222] Embodiment B45. Provided is the method of any one of embodiments B27 to B44,wherein the arachidonic acid composition is administered orally.

[0223] Embodiment B46. Provided is the method of any one of embodiments B25, whereinthe method further comprises simultaneously or sequentially administering one or more myeloid growth factors to said patient. In embodiments, the one or more said myeloid growth factors is selected from the group consisting of granulocyte macrophage colony-stimulating factor (GM- CSF), granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF) and interleukin-3. In embodiments, the one or more myeloid growth factors is selected from filgrastim, filgrastim-sndz, tbo-filgrastim, pegfilgrastim, pegfilgrastim, lenograstim, argramostim, and molgramostim.

[0224] Scoring systems can be used to identify chemotherapy patients most at risk fordeveloping complications of neutropenia. American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), Infectious Disease Society of America (IDSA), and European Society of Medical Oncology (ESMO) recommend using the Multinational Association for Supportive Care in Cancer (MASCC) score to risk stratify patients (See Bhardwaj et al. Support Care Cancer 2021 Mar 24;29(10):5905–5914). The helps to quantify the risk of FN- - 43 - 1104747404\8\AMERICASrelated complications. Higher scores indicate lower risk, with a maximum of 26 points. A MASCC scoring system is provided below: Indicator Scoring Burden of illness (symptom severity) None or mild: 5 points s ighrisk (< 21 points) for serious FN-related complications (Bhardwaj et al.).

[0225] Current guidelines suggest prophylactic intervention (for example, by administrationof granulocyte colony-stimulating factor (G-CSF)) when the patient's risk of neutropenia exceeds 20% on the MASCC risk index (Hughes et al. Clinical decision support for chemotherapy-induced neutropenia using a hybrid pharmacodynamic / machine learning model, CPT Pharmacometrics Syst Pharmacol. 2023;12:1764–1776). Other models may also be used to assess risk (Hughes et al.).

[0226] Scoring systems, including the MASCC scoring system, can be used to identifypatients who would benefit from the treatments of neutropenia provided herein, including in any of the claims or embodiments.

[0227] Provided herein is a method of alleviating gastrointestinal toxicity, the methodcomprising: administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments A to A13e and B1 to B26 to a patient in need thereof; optionally wherein the gastrointestinal toxicity results in at least one symptom selected from mucositis and / or diarrhea. - 44 - 1104747404\8\AMERICASArticles of Manufacture and Kits

[0153] Also provided are articles of manufacture and kits comprising a pharmaceuticalcomposition which comprises arachidonic acid of high purity and / or one or more esters thereof, for use in any of the methods described herein. EXAMPLES Example 1a:Myeloprotection Study

[0154] Purpose: investigate the impact of arachidonic acid on blood counts followingchemotherapy in the presence or absence of granulocyte colony-stimulating factor (G-CSF) after 2 weeks of chemotherapy.

[0155] Hypothesis: Increasing arachidonic acid levels will improve resilience tochemotherapy as evidenced by higher neutrophil count after second round of chemotherapy. Table A. Group Chemo G-CSF Diet1 5-FU 150 mg / kg qw x 2w - Control

[0156] An arachidonic acid rich diet is initiated 4 weeks before initiating chemotherapy (day0) in a mouse model. The control diet can be purified diet with 7% (w / w) soybean oil added. The ARD diet can be purified diet with 3% (w / w) ARASCO® oil and 4% (w / w) soybean oil added. On day, 28 chemotherapy is begun. On day 30, G-CSF or vehicle is delivered. Body weights are measured daily beginning day 28 (or as close to daily as operationally reasonable). The test groups are split each into group 5 and 5, where Group A: CBC day 39 (11 days after chemo) - Terminal bleed day is 46 (18 days after chemo) for CBC + EDTA; plasma is collected; Group B: CBC day 42 (14 days after chemo) - Terminal bleed day 49 (21 days after chemo) for CBC + EDTA; plasma is collected. - 45 - 1104747404\8\AMERICASExample 1b: Myeloprotection Study

[0157] Various diets with matched fiber content were evaluated in the context of 5-FUtreatment in naive female CS7BL / 6 mice. Whole blood, plasma and GI tract were collected for downstream analysis outside the scope of this study. Group No.Administered Route Schedule Dosage Animals

[0158] Animals were distributed into treatment groups such that the mean body weight in eachgroup is within 10% of the overall mean. Animals were held for 3 weeks post administration of 5-FU to assess delayed toxicity response and sample collection.

[0159] Four different rodent food containing matched dietary fiber and varying amounts / typesof dietary fat were used. Standard diet was purified diet with 7% (w / w) soybean oil added. Ketogenic diet was 23% Crisco, 32.5% CocB, 8.5% SBO. ARD is purified diet with 3% (w / w) ARASCO® oil and 4% (w / w) soybean oil added.

[0160] All mice were maintained on their respective diets until individual endpoints or studytermination, whichever came first. Body weights were measured 3x / week from Day 0-27.

[0161] Survival Blood Sampling: Groups 1-5: On Days 35 and 42, collect 200 µL of wholeblood from Mice#1-5 and Mice#6-10, respectively - 46 - 1104747404\8\AMERICAS

[0162] Terminal Blood Sampling: Groups 1-5: On Days 38 and 50, collect full terminal bloodvolume from Mice#1-5 and Mice#6-10, respectively. Remove 200 µL for testing

[0163] Mice were pre-treated for 4 weeks with Standard diet, Ketogenic diet, or ARD, asindicated above, then given one dose of 5-FU chemotherapy (150 mg / kg 5-FU). Blood was drawn on day 7, 10, 14, and 21. Figure 1 provides neutrophil count. As can be seen, faster neutrophil recovery was observed in animals that consumed ARD prior to chemotherapy.Example 2: Impact on Standard of Care

[0164] Purpose: investigate impact of arachidonic acid on growth of tumor and tolerance oftreatment in standard tumor x chemotherapy models with moderate to severe treatment toxicity

[0165] Hypothesis: Increasing arachidonic acid levels will increase tolerance ofchemotherapy, as evidenced by reduced weight loss without negatively impacting tumor progression

[0166] Initiate diet for all mice 3 weeks prior to tumor implantation. Control diet can bepurified diet with 7% (w / w) soybean oil added. ARD is purified diet with 3% (w / w) ARASCO® oil and 4% (w / w) soybean oil added. Group Chemo Tumor Diet

[0167] Bodyweights are measured daily (or as close to daily as operationally reasonable) fromtime of tumor implantation. 14 days after chemotherapy initiation CBC samples are taken. Humane endpoint: Tumor and plasma are collected for analysis. - 47 - 1104747404\8\AMERICASExample 3: Preparation of arachidonic acid and / or one or more esters thereof or an arachidonic acid composition

[0168] Arachidonic acid can be prepared according to procedures known by one of ordinaryskill in the art or can be purchased, for example, from Millipore Sigma / Sigma Aldrich Cat. No. 181198.

[0169] Arachidonic acid esters can be prepared according to procedures known by one ofordinary skill in the art or can be purchased, for example, from Aurora Fine Chemical, Item No. isopropyl ester (119524-26-4); from A2B Chem, Item No. AC77797, n-propyl ester (93913-74- 7); from Millipore Sigma / Sigma Aldrich Cat. No. A9135, ethyl ester; and from Cayman Chemical, Item No.90014, methyl ester.

[0170] An arachidonic acid monoglyceride can be prepared according to procedures knownby one of ordinary skill in the art or can be purchased, for example, from Cayman Chemical, Item No.62150, ≥95% pure as a 9:1 mixture of 1-AG and 2-AG; from A2B Chem, Item No. BD35707, as the S-isomer of 1-AG (124511-15-5); from Aurora Fine Chemicals, Item No. 153.211.030, as the R-isomer of 1-AG (129783-94-4); and from Cayman Chemical, Item No. 62160, 2-AG (53847-30-6).

[0171] An arachidonic acid diglyceride can be prepared according to procedures known byone of ordinary skill in the art or can be purchased, for example, Cayman Chemical, Item No. 26936, 1,3-AG (95034-09-6); from Aurora Fine Chemicals, Item No. 194.901.239, 1,2-AG (129691-19-6); from Aurora Fine Chemicals, Item No. 194.754.362, as the S-isomer of 1,2-AG (64111-11-1).

[0172] An arachidonic acid triglyceride can be prepared according to procedures known byone of ordinary skill in the art or can be purchased, for example, Cayman Chemical, Item No. 10009826, 1,2,3-AG (23314-57-0). Example 4: Screening of Emulsifying Agents, Co-solvents, Stabilizers, and Pharmaceutically Acceptable Oils

[0173] A capsule liquid fill composition that improves the systemic blood levels ofarachidonic acid (AA) will be identified. This overcomes a limitation with a current form of AA (ARASCO®) that has only 40% potency (i.e.40% arachidonic acid derived from its various forms in the composition), that comprises many other compounds, and that may not have optimal properties for oral absorption.

[0174] A liquid composition for capsule filling with >70% arachidonic acid of high purity oran ester thereof of high purity is used, preferably in the range 80-90% arachidonic acid of high - 48 - 1104747404\8\AMERICASpurity or an ester thereof of high purity in the liquid. The final loading of arachidonic acid of high purity or an ester thereof of high purity in the liquid formulation is dictated by 1) potency of arachidonic acid of high purity or an ester thereof of high purity added (for example 95% purity) plus 2) the amount of excipient added (for example 10% excipient).

[0175] Pharmaceutically acceptable excipients to be added to the arachidonic acid of highpurity or an ester thereof of high purity ingredient are screened. The excipients are selected to provide a “self-emulsifying system” - meaning a mixture of an optional diluent (i.e. an optional pharmaceutically acceptable oil) + an emulsifying agent + co-solvent + an optional stabilizer that together help disperse the liquid after it is taken orally.

[0176] A self-emulsifying system may improve the dispersion of arachidonic acid of highpurity or an ester thereof of high purity in the gastro-intestinal tract, presenting it to the body in a more absorbable form. Rapid emulsification may also facilitate absorption, as arachidonic acid of high purity or an ester thereof of high purity will be dispersed faster compared to a neat (unformulated) form of arachidonic acid of high purity or an ester thereof of high purity.

[0177] Chemical compatibility test. Compatibility is measured by storing the test samples atcontrolled temperature (e.g. an oven set to 40 °C or refrigerator set to 5oC). Testing is performed at pre-defined hold times by two methods - visual appearance and arachidonic acid of high purity or an ester thereof of high purity chemical purity measured by GC or other chromatographic method. Additional methods of determining chemical compatibility and stability are known to the person of ordinary skill in the art. Example 4a

[0178] To choose excipients, some or all of these experiments can be conducted:

[0179] The test samples are prepared by combining AA (and / or ester thereof) with anemulsifying agent at a ratio of from about 1 / 10 to about 1 / 1, and optionally adding a cosolvent, a stabilizer, and / or a pharmaceutically acceptable oil The samples are vigorously mixed for a short period of time either manually, with a vortexer, or magnetic stir bar.

[0180] Miscibility test. The test samples are screened by measuring miscibility with thearachidonic acid and / or one or more esters thereof. The test samples are visually examined after mixing, to see if there is phase separation of the components (signaling immiscible mixture) or if a single phase remains (signaling a miscible mixture).

[0181] In vitro dispersion test. This test is performed by adding a single dose of formulationinto a standardized aqueous media that undergoes mild stirring with a paddle or magnetic stir bar. An example media is 500 mL 0.1N HCl with temperature controlled close to body temperature of - 49 - 1104747404\8\AMERICAS37°C. The target in vitro behavior is the formation of a dispersed oil in water colloid with a milky or cloudy appearance, which indicates self-emulsification. Example 4b

[0182] Preliminary arachidonic acid as a free fatty acid (AA FFA) liquid formulations wereprepared using > 98% pure arachidonic acid and were studied using an in vitro dispersion test at 50 mL scale (formulations and data not shown). Samples containing 25-40% excipient, with the remaining content being arachidonic acid, were evaluated based on the appearance of dispersed phase in the test media (water). Table 1. Description Sample Volume / Media Volume Observations te%pure arachidonic acid) projected for humans means that a level of >20% excipient in a formulation corresponds to the excipient dose exceeding 1 g. This quantity could cause tolerability and safety issues. Typical pharmaceutical SEDDS compositions contain 60-90% excipients, which are feasible because the oral dose is typically lower than for AA FFA (> 98% pure arachidonic acid). However, the typical pharmaceutical SEDDS approach is not suited to a high-dose AA FFA product.

[0184] Therefore, a series of experiments were designed to identify dispersion-enhancingexcipients that function at significantly lower concentrations than usually used for SEDDS.

[0185] Initially, formulations containing 20% excipient(s) were tested to identify dispersion-enhancing excipients that function well without exceeding 1 g excipient(s) of a projected 5 g AA FFA (> 98% pure arachidonic acid) dose. Test media was Fed State Simulated Intestinal Media (FeSSIF). Surprisingly, as detailed below, multiple excipients were identified that showed dispersion-enhancing behavior at 5% and even 2.5% concentrations. For a 5 g AA FFA (> 98% pure arachidonic acid) dose, these excipient levels equate to 250 mg (5%) an 125 mg (2.5%).

[0186] Further in vitro assessment of Formulation prototypes were investigated as detailedbelow. Experimental

[0187] Standardized ranking of dispersibility was done according to the turbidity of thesolution. Turbidity was assessed visually, but can also be assessed with a UV spectrophotometer - 50 - 1104747404\8\AMERICASor other means known to the person of ordinary skill in the art. Upon visual assessment, a turbidity score was assigned to allow ranking of different excipients. Turbidity was expressed as NTU (nephelometric turbidity units).

[0188] The media was modified to use a biorelevant media for two reasons 1) AA FFA ishighly hydrophobic, and so testing in aqueous media with no surfactant tends to cause sample to stick to surfaces, and 2) it is projected that an AA FFA composition, including the arachidonic acid of high purity and / or one or more esters thereof of high purity, will be administered in the fed state – therefore biorelevant media are closer to the in vivo condition.

[0189] FeSSIF media was selected as the primary test media. Experiments were alsoperformed with Fasted State Simulated Intestinal Fluid (FaSSIF) for reference. FeSSIF media is a pH 5.5 buffer containing bile salts at physiological levels.

[0190] The test procedure was as follows. 1 mL test media was added to a 8 mL glass vial.20µL AA sample (> 98% pure arachidonic acid) was added via pipette to the test media. The vial was closed and manually shaken for 1-2 seconds. The vial was placed on flat surface, and after 10-20 seconds, visual assessment of turbidity was made, and any other noticeable physical effects were noted. The experiment was performed at room temperature,

[0191] Samples that exhibited high turbidity, for example cloudy or white suspensions, werejudged to have excellent dispersibility. Although the colloid phase causing turbidity was not analyzed, the colloid is assumed to include fine particle size of AA FFA because AA FFA is highly unlikely to precipitate due to its low melting temperature. The colloid creating turbidity may consist of emulsified AA FFA in the micron or nanosize ranges, and / or colloidal mixtures of AA FFA, excipient and bile salts. All of these phases, if formed in vivo, have potential to enhance absorption of AA FFA through surface area increase, and via more extensive transport of AA FFA to and through the absorptive mucosa. Results - Excipient dispersibility screen

[0192] Nineteen excipients were added to AA FFA at a level of 20% excipient. All sampleswere tested for dispersibility. Results are tabulated below. Table 2. Excipient Chemistry HLB Fed Dispersibility- 51 - 1104747404\8\AMERICASExcipient Chemistry HLB Fed Dispersibility (20% Additive) Vi l NTUand diversechemical structure, and included both liquid and solids. Surprisingly, the successful excipients were not predicted. Specifically, hydrophilic-lipophilic balance (HLB) value does not seem to correlate with good dispersibility, nor does the fatty acid (FA) chain length (for lipid-based excipients) and no seeming correlation based on the presence of PEG or glyceride. The high- - 52 - 1104747404\8\AMERICASperforming excipients were not predictable. However, it was observed that four of the lead excipients (Vit E TPGS, Plurol® Oleique, Tween™ 80, and phosphatidyl choline) are all non- ionic surfactants, they are all emulsifying agents, and all have larger molecular weight (>700 Da).

[0194] Nine lead excipients (2, 3, 10, 11, 14, and 16-19 in the above table) progressed intoadditional testing. Experiments were performed to see if even lower levels of additive could aid dispersion of the very hydrophobic AA FFA (> 98% pure arachidonic acid). A number of excipients could improve dispersion as low as 5% and 2.5% concentration of excipient in AA FFA. Tables 3a and 3b provide these additional formulations and dispersibility results. Table 3a. Table 3a Dispersibility (Visual) Fed state Fed state 5% Fasted state Fed state eTable 3b Dispersibility (NTU) Fd tt Fd tt 5% F td tt Fd tt e

[0095] ase on resu s n a e a- , our excpens were en e or ur er es ng – heircapability of achieving measurable dispersion improvement at low concentration and in combinations of excipients. These were Plurol®Oleique, Tween®80, Vit E TPGS, and phosphatidyl choline. - 53 - 1104747404\8\AMERICAS

[0196] To explore if there may be flexibility or further enhancement in dispersion by usingcombinations of the lead dispersing-agents, a series of two-excipient mixtures were made to provide a total excipient concentration of 5%.

[0197] See Tables 4a and 4b – the two-excipient mixtures (two emulsifying agents) providedgood dispersion in all cases. Surprisingly, the good dispersion was even evident in the fasted state measurement, in all cases providing even better dispersion scores than the good scores for single- excipients measured in the fasted state. Table 4a. Dispersibility 2.5% 2.5% Fed state FastedTable 4b Dispersibility 2.5% 2.5% Fed state Fastedi.e.ARASCO®Oil). The dispersion of ARASCO®Oil (only) in FeSSIF and FaSSIF is low, significantly lower compared to the AA-FFA samples in Tables 3a / b and 4a / b. Data not shown.

[0199] These data support progression of high concentration, high purity AA FFAcompositions into non-clinical tests. Formulations containing 5% single-additive and 2.5% / 2.5% combinations are dosed in two mice studies:- Single-dose study – measuring total fatty acid between 0-24 hours post-dose- Multi-dose study – measuring free fatty acid on Day 0 and Day 7

[0200] Neat ARASCO® oil and neat arachidonic acid of high purity and / or one or more estersthereof of high purity dosed as controls by oral gavage. Analysis can be performed if new compositions match or improve upon systemic AA levels achieved by ARASCO®oil. - 54 - 1104747404\8\AMERICAS

[0201] Short term chemical stability tests can also be performed to measure the impact of theexcipient(s) on stability, as well as the impact of stabilizer(s) added at 0.1% or lower to the liquid composition. Example 4c

[0202] Arachidonic acid ethyl ester compositions containing 20% or 5% excipient were testedfor dispersion using the FeSSIF method used previously (described in Example 4b). These data demonstrate that the selected excipients also have positive dispersion enhancement for the ethyl ester of AA, with either mid or high dispersibility seen at both excipient levels. Table 5a Dispersibility 20% excipient 5% excipientTable 5b Dispersibility 20% excipient 5% excipient

[0203] Example 5: In Vivo Canine Study

[0204] One formulation will be tested in an in vivo canine assay to assess oralpharmacokinetics (PK) of the fill in a two-piece capsule. The composition for testing includes: Arachidonic Acid of high purity and / or 70-100% t th f ty ne nele- 55 - 1104747404\8\AMERICAS

[0205] This study will assess the absorption of arachidonic acid of high purity and / or one ormore esters thereof of high purity in a formulation as provided herein and compare to ARASCO® Oil, as well as assess the feasibility of reducing the “pill burden” associated with a product such as ARASCO® Oil.

[0206] Test articles may include:Test Article A: ARASCO® capsule (250 mg) Test Article B: ARASCO® capsule (500 mg) Test Article C: capsule containing neat arachidonic acid of high purity (250 mg) Test Article D: capsule containing neat arachidonic acid of high purity formulated as SEDDS (250 mg) Test Article E: capsule containing neat arachidonic acid ethyl ester of high purity (250 mg) Test Article F: capsule containing neat arachidonic acid ethyl ester of high purity formulated as SEDDS (250 mg)

[0207] A single dose of the test article will be administered to fasted (pentagastrintreated) beagle dogs (N=4). Plasma samples will be taken at time points from 0-24 hours and PK data will be obtained. Example 6a: Alopecia Study

[0208] Chemotherapy-Induced Alopecia is a condition of hair loss seen in the clinic.When modeled in mice, it has proven to be an effective means of understanding the biology of this form of hair loss. See Paus, et al. Chemotherapy-induced alopecia in mice. Induction by cyclophosphamide, inhibition by cyclosporine A, and modulation by dexamethasone, The American Journal of Pathology, 1994, 144(4), 719. (“Paus et. al.1994”).

[0209] This study investigates the effect of ARASCO® oil in topical or diet formulationon improving regrowth in a cyclophosphamide-inhibited hair growth mouse model. Abbreviations used in this example ANOVA: Analysis of variance CP: Cyclophosphamide HG: Hair Growth IACUC: Institutional animal care and use committee IHC: Immunohistochemistry IP: Intraperitoneal route of administration IV: Intravenous route of administration mg / kg: Milligrams / kilogram mg / mL: Milligrams / milliliter - 56 - 1104747404\8\AMERICASmL / kg: Milliliters / kilogram MSDS: Material safety data sheet PO: Oral route of administration QD: Once per day administration SEM: Standard error of the mean SOP: Standard operating procedure TA: Test article TBD: To be determined Experimental Procedures

[0210] Female C57Bl / 6 mice (obtainable from Charles River Labs), aged 6 weeks onarrival, were used in this study. Animal procedures were conducted according to established protocols approved by the IACUC committee. Animals were assigned randomly to treatment groups. Each mouse was single-housed on a 12 hr light / dark cycle (lights on 7:00 AM) and fed for 3 weeks on control diet and water ad libitum during the acclimation phase. During the study phase, mice were fed control diet 1, control diet 2, or ARASCO®oil enriched diet and water ad libitum, as indicated in the table below. The following were administered: ^cyclophosphamide (CP in vehicle: 0.9% saline): IP (10 mL / kg);^ topical 2% arachidonic acid as a free fatty acid (AA FFA) of high purity in vehicle (48%ethanol, 30% glycerol, 21.5% dH2O, 0.5% lactic acid) (100 µL / mouse) ^ARD 1: control diet 1 with 3% (w / w) ARASCO oil and 4% soybean oil added^ ARD 2: control diet 2 with 12% (w / w) ARASCO oil and 13% (w / w) soybean oil added^ Topical Minoxidil: 5% minoxidil in vehicle (48% ethanol, 30% glycerol, 21.5% dH2O, 0.5%lactic acid) 100 µL / mouse,); ^vehicle: topical (100 µL / mouse).^ Control diet 1: purified diet with 7% (w / w) soybean oil added^ Control diet 2: purified diet with 25% (w / w) soybean oil added

[0211] Dose frequency for were QD. Study duration was 26 days + 3 weeks acclimationand the number of animals per group is 10. - 57 - 1104747404\8\AMERICASStudy Design Table

[0212] In the table below, A is hair depilation and B is vehicle.Group Treatment Diet Days of Dosing Dose Route CP1 A C ntr l di t 1 N / A - afterp p g , , .

[0213] During the 3-week acclimation period, for Group 1-4 and Group 8-11, based onbody weights, mice were randomized into 8 diet treatment groups, fed with either control diets (control diet 1 & 2) or ARASCO oil enriched diets (ARD diet 1 & 2) according to the above table. All the rest of mice were fed with the control diet 1. The diet treatment for each group were continued throughout the entire study.

[0214] Hair depilation and CP injection: Mice were depilated on their back on Day 0causing hair follicles to enter the Anagen phase. Animals were anesthetized with isoflurane and hair on their backs was removed by wax depilation. Animals were evaluated to determine if - 58 - 1104747404\8\AMERICASthere was pigmentation present beneath the hair. If there was pigmentation, nicks, cuts or scars from fighting, these animals were excluded from the study. Baseline (Day 0) scores were taken for each mouse immediately after depilation. For Group 8-14, cyclophosphamide (CP) at 120 mg / kg were administrated via single IP injection on day 8. This dose has been demonstrated in the literature to cause alopecia (Paus et. al 1994).

[0215] Dosing: The topical dosing of Vehicle, Minoxidil, or 2% AA FFA was startedfrom either Day 1 (for Group 1-7) or day 8 (prior to CP injection, for Group 8-14). The topical dose volume was 100 µL / mouse.

[0216] Evaluation: During the entire study including acclimation time, all mice weremeasured for body weight changes, twice per week. Mice were evaluated for hair depilation on Day 0 for all Groups. Mice were visually scored based upon hair growth using the scale below on days (0, 4, 8, 11, 13, 15, 18, 20 and 26). Hair Growth Scoring Criteria nt ntanizedand a skin patch approximately 2cm2at the site of the depilation were collected and fixed in 10% formalin for further histological evaluation and optional IHC analysis of hair follicle stem cell markers.

[0218] Data Analysis: Data for each quantitative endpoint were presented as the average± SEM. Differences between vehicle control and each treatment groups were determined by Ordinary one-way ANOVA with Dunnett’s multiple comparison test OR 2-way ANOVA with - 59 - 1104747404\8\AMERICASDunnett’s multiple comparison test using GraphPad Prism (current version) with an alpha threshold of 0.05.

[0219] Data are provided in Figure 5a where Group 1 was control diet 1 and Group 2was ARD 1. Example 6b: Alopecia Study

[0220] Mice were pre-treated for 2 weeks with ARD (purified diet with 3% ARASCOoil and 4% soybean oil added) or control diet (purified diet with 7% (w / w) soybean oil).. Diet treatments continued after chemotherapy regimen.

[0221] Chemotherapy was 5-FU (150mg / kg) + Oxa (6mg / kg) administered once perweek. Hair loss observation was made after second chemotherapy injection. Mice treated with ARD showed resistance to chemotherapy-induced hair loss.

[0222] Figure 5b shows mice treated with ARD and with control diet.Example 7: Neutropenia Study

[0223] INTRODUCTION

[0224] ARA (powder made from ARASCO® oil) is dry Mortierella Alpina oil, high inAA, on gum acacia and hydrolyzed pea protein, containing less than 2% of mixed tocopherols and with rosemary extract added to preserve freshness. ARD is purified diet with 3% ARASCO oil and 4% soybean oil added. ARA is purified diet with 3% ARASCO powder and 4% soybean oil added. Control diet is purified diet with 7% soybean oil added.1.2% w / w AA free fatty acid diet is purified diet with 1.2% w / w AA free fatty acid (99% purity) and 5.8% soybean oil added. Group Chemotherapy Agent

[0225] C57BL6 / J mice were fed daily: control diet, ARD, ARA, or 1.2% w / w AA freefatty acid diet. On Days 7 and 14 blood was collected. On Day 14, 3 male and 3 female mice from each of Groups 1-4 were treated with 3 doses of 100 mg / kg 5-FU every 3 days. - 60 - 1104747404\8\AMERICAS

[0226] Neutrophils, red blood cell, and hemoglobin were measured by complete bloodcounting system. Data are provided in Figures 2a to 2d. FFA in the figures corresponds to 1.2% (w / w) AA free fatty acid diet. As can be seen, all 1.2% w / w AA containing diets (ARD, ARA and AA FFA) improved the levels of neutrophil, red blood cell and hemoglobin after chemotherapy regimen. Example 8: Neutropenia Study

[0227] INTRODUCTIONGroup Chemotherapy Agent Protocol Day 1: blood collection se e se e

[0228] C57BL6 / J mice, injected with MC38 cells (colorectal cancer cell line), were fedcontrol diet (purified diet with 7% w / w soybean oil) or ARD (purified diet + 3% ARASCO®oil and 4% soybean oil added) for two weeks and injected intraperitoneally with 150mg / kg 5-FU + 6mg / kg oxaliplatin every two weeks . Blood collections were taken as indicated in the table above. Collected blood was analyzed for neutrophil, white blood cell (WBC), lymphocyte, red blood cell, and hemoglobin counts. Data are provided in Figures 3a to 3e. As seen in the data, ARD treatment enhanced the levels of neutrophils, WBC, lymphocytes, red blood cells and neutrophils, especially after the second chemotherapy injection, compared to control mice. Example 9: Bone marrow stem / progenitor cells and platelets study

[0229] Mice are treated with control diet (purified diet with 7% (w / w) soybean oiladded) or ARD (purified diet + 3% ARASCO®oil and 4% w / w soybean oil) for 2 weeks prior to administration of 5FU (250mg / kg). - 61 - 1104747404\8\AMERICASGroup Chemotherapy agent1 3 control mice (vehicle, no ARD), 3 mice dosed with ARD none2 4 t l i hi l ARD 4 i d d ith ARD 50 k 5FUs,oe a o s ee a ese a sa e a o es o ca , c- a eage markers (L). Percentage of Lineage-, Sca1+, c-kit+ cells (% LSK) and their numbers (# LSK) were measured by flow cytometry and data provided in FIG.4a. After 3 days, blood platelets were measured and data provided in FIG.4b. As seen in the data, ARD enhanced the levels of both % LSK, # LSK and platelets after chemotherapy. In all figures, C is control diet Example 10: Anti-oxidant assessment

[0231] High-purity Arachidonic Acid samples were stored at controlled temperature with andwithout butylated hydroxytoluene (BHT) dissolved in the oil. Samples were stored in glass vials. Following 4 weeks storage, samples were tested using an HPLC analytical method (method information is tabulated below). Results are expressed as the % Arachidonic Acid by comparing HPLC peak area of the sample against an AA reference standard. The data show that increasing BHT content reduces the degree of AA loss through chemical degradation.

[0232] Analytical method instrument conditionsParameter Setting

[0233] nay ca me o gra enTime (mins) % Mobile Phase A % Mobile Phase B- 62 - 1104747404\8\AMERICASTime (mins) % Mobile Phase A % Mobile Phase B 22.0 10 90

[0234] Sample % Arachidonic Acid at 4 wksArachidonic Acid (Control) 22.7%

[00235] While certain embodiments of the present invention have been shown and describedherein, it will be obvious to ordinarily skilled artisans that these embodiments are merely exemplary. Numerous variations, changes, and substitutions will occur to ordinarily skilled artisans within the scope and spirit of the invention. Various alternatives to the described embodiments may be employed. Accordingly, the invention should be considered as limited only by the scope of the following claims, and that methods and structures within the scope of these claims and their equivalents are covered. - 63 - 1104747404\8\AMERICAS

Claims

1. Claims:

1. A pharmaceutical composition, comprising: arachidonic acid of high purity and / or one or more esters thereof of high purity; and one or more pharmaceutically acceptable excipients independently selected from the group consisting of an emulsifying agent, a pharmaceutically acceptable oil or pharmaceutically acceptable wax, and a co-solvent; and additionally comprising an optional stabilizer.

2. The pharmaceutical composition of claim 1, comprising arachidonic acid of high purity and / or one or more esters thereof of high purity; one or more emulsifying agents; one or more optional co-solvents; one or more optional stabilizers; and one or more optional pharmaceutically acceptable oils.

3. The pharmaceutical composition of any one of claims 1 to 2, comprising a) about 70 wt / wt% to about 98.5 wt / wt% of arachidonic acid of high purity and / or oneor more esters thereof of high purity; in embodiments, about 90 wt / wt% to about 99.5 wt / wt%; b) about 0.5 wt / wt% to about 20 wt / wt% in total of one or more emulsifying agents;in embodiments, about 0.5 wt / wt% to about 10 wt / wt%; c) one or more optional co-solvents, wherein when present is present in about 0.5wt / wt% to about 10 wt / wt% in total; in embodiments, about 0.5 wt / wt% to about 10 wt / wt% in total; d) one or more optional stabilizers, wherein when present is present in about 0.001wt / wt% to about 1 wt / wt% in total; and e) one or more optional pharmaceutically acceptable oils, when present is present inabout 0.5 wt / wt% to about 20 wt / wt% in total; in embodiments, about 0.5 wt / wt% to about 10 wt / wt%; wherein the wt / wt% of the arachidonic acid of high purity and / or one or more esters thereof of high purity, the emulsifying agent(s), the optional co-solvent(s), the optional stabilizer(s), and the optional pharmaceutically acceptable oil(s) total 100 wt / wt%.

4. The pharmaceutical composition of claim 1, comprising 1) about 90 wt / wt% to about 99.5 wt / wt% of arachidonic acid of high purity and / or oneor more esters thereof of high purity; and a) about 0.5 wt / wt% to about 10 wt / wt% in total of one or more emulsifying agents;or - 64 - 1104747404\8\AMERICASb) about 0.5 wt / wt% to about 10 wt / wt% in total of one or more pharmaceuticallyacceptable oils; or c) about 0.5 wt / wt% to about 10 wt / wt% in total of one or more co-solvents;and 2) one or more optional stabilizers, wherein when present is present in about 0.001wt / wt% to about 1 wt / wt% in total; and wherein the wt / wt% of 1), a), and 2) total 100 wt / wt%; the wt / wt% of 1), b), and 2) total 100 wt / wt%; and the wt / wt% of 1), c), and 2) total 100 wt / wt%.

5. The pharmaceutical composition of any one of claims 1 to 4, comprising arachidonic acid of high purity and / or one or more esters thereof of high purity; one or more emulsifying agents; and one or more optional stabilizers; and optionally wherein the pharmaceutical composition does not comprise a pharmaceutically acceptable oil or pharmaceutically acceptable wax, and additionally optionally wherein the pharmaceutical composition does not comprise a co- solvent.

6. The pharmaceutical composition of claim 1 or 4, comprising arachidonic acid of high purity and / or one or more esters thereof of high purity; one or more pharmaceutically acceptable oils or pharmaceutically acceptable waxes; and one or more optional stabilizers; wherein the pharmaceutical composition does not comprise an emulsifying agent and additionally optionally wherein the pharmaceutical composition does not comprise a co-solvent.

7. The pharmaceutical composition of claim 1 or 4, comprising arachidonic acid of high purity and / or one or more esters thereof of high purity; one or more co-solvents; and one or more optional stabilizers; wherein the pharmaceutical composition does not comprise an emulsifying agent and additionally optionally wherein the pharmaceutical composition does not comprise a pharmaceutically acceptable oil or pharmaceutically acceptable wax.

8. The pharmaceutical composition of any one of claims 1 to 5, wherein one or two emulsifying agents are present and are independently selected.

9. The pharmaceutical composition of any one of claims 1 to 5 and 8, wherein the emulsifying agent(s) are independently selected from the group consisting of a polysorbate 20; polysorbate 80; PEG-40 hydrogenated, ethoxylated castor oil; lauroyl polyoxyl-32 glycerides; caprylocaproyl polyoxyl-8 glycerides; caprylocaproyl polyoxyl-8 glycerides; oleoyl polyoxyl-6 glycerides; mono-, di- and triglyceride esters of fatty acids (C8to C18), the triester fraction being predominant (“hard fat”); polyglyceryl-3 dioleate; sorbitan monopalmitate 40; sorbitan monostearate 60; propylene glycol monocaprylate NF [may also be labeled as propylene glycol monocaprylate (type - 65 - 1104747404\8\AMERICAS II) NF until December 1, 2026]; a-tocopherol poly-ethylene glycol succinate; phosphatidyl choline; and lyso-phosphatidyl choline.

10. The pharmaceutical composition of any one of claims 1 to 5 and 8 to 9, wherein at least one or exactly one of the emulsifying agent(s) is a polysorbate 80.

11. The pharmaceutical composition of any one of claims 1 to 5 and 8 to 9, wherein at least one or exactly one of the emulsifying agent(s) is a PEG-40 hydrogenated, ethoxylated castor oil.

12. The pharmaceutical composition of any one of claims 1 to 5 and 8 to 9, wherein at least one or exactly one of the emulsifying agent(s) is lauroyl polyoxyl-32 glycerides.

13. The pharmaceutical composition of any one of claims 1 to 5 and 8 to 9, wherein at least one or exactly one of the emulsifying agent(s) is caprylocaproyl polyoxyl-8 glycerides.

14. The pharmaceutical composition of any one of claims 1 to 5 and 8 to 9, wherein at least one or exactly one of the emulsifying agent(s) is oleoyl polyoxyl-6 glycerides.

15. The pharmaceutical composition of any one of claims 1 to 5 and 8 to 9, wherein at least one or exactly one of the emulsifying agent(s) is mono-, di- and triglyceride esters of fatty acids (C8to C18), the triester fraction being predominant.

16. The pharmaceutical composition of any one of claims 1 to 5 and 8 to 9, wherein at least one or exactly one of the emulsifying agent(s) is a polysorbate 20.

17. The pharmaceutical composition of any one of claims 1 to 16, wherein the emulsifying agent(s) is present in a total amount selected from about 5% to about 10% or selected from about 2% to about 6% or selected from about 2.5% and about 5%.

18. The pharmaceutical composition of any one of claims 1 to 17, wherein at least one or exactly one of the co-solvent(s), when present, is selected from a polyethylene glycol (in embodiments PEG400) or a propylene glycol.

19. The pharmaceutical composition of any one of claims 1 to 18, wherein the co-solvent(s), when present, is present in a total amount selected from about 5% to about 10% or selected from about 2% to about 6% or selected from about 2.5% and about 5%.

20. The pharmaceutical composition of any one of claims 1 to 19, wherein a co-solvent(s) is present and optionally wherein one co-solvent is present.

21. The pharmaceutical composition of any one of claims 1 to 20, wherein at least one or exactly one of the optional stabilizer(s), when present, is selected from is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and d-alpha-tocopherol. - 66 - 1104747404\8\AMERICAS22. The pharmaceutical composition of any one of claims 1 to 21, wherein the stabilizer(s), when present, is present in a total amount selected from about 0.01% to about 0.025% or selected from about 0.01% to about 0.1% or selected from a non-zero amount of 0.1% or less.

23. The pharmaceutical composition of any one of claims 1 to 22, wherein a stabilizer(s) is present and optionally wherein one stabilizer is present.

24. The pharmaceutical composition of any one of claims 1 to 23, wherein at least one or exactly one of the pharmaceutically acceptable oil(s), when present, is selected from one or more fatty acid glycerides (including mono-, di or tri-glycerides), and / or one or more free fatty acids.

25. The pharmaceutical composition of any one of claims 1 to 24, wherein the pharmaceutically acceptable oil(s), when present, is present in a total amount selected from about 5% to about 10% or selected from about 2% to about 6% or selected from about 2.5% and about 5%.

26. The pharmaceutical composition of any one of claims 1 to 25, wherein the arachidonic acid of high purity and / or esters thereof of high purity is arachidonic acid of high purity.

27. The pharmaceutical composition of any one of claims 1 to 26, wherein the arachidonic acid of high purity and / or one or more esters thereof of high purity is a combination of arachidonic acid of high purity and one or more esters of arachidonic acid of high purity; preferably wherein the one or more arachidonic acid esters of high purity is arachidonic acid ethyl ester of high purity.

28. The pharmaceutical composition of any one of claims 1 to 26, wherein the arachidonic acid of high purity and / or one or more esters thereof of high purity is either arachidonic acid of high purity or one or more esters of arachidonic acid of high purity; preferably wherein the one or more arachidonic acid esters of high purity is arachidonic acid ethyl ester of high purity.

29. The pharmaceutical composition of any one of claims 1 to 26, wherein the arachidonic acid of high purity and / or one or more esters thereof of high purity is one or more esters of arachidonic acid of high purity; preferably wherein at least one is arachidonic acid ethyl ester of high purity.

30. The pharmaceutical composition of any one of claims 1 to 28, wherein the arachidonic acid of high purity has a purity of about 80% or greater, about 85% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, or about 99% or greater as measured by GC. - 67 - 1104747404\8\AMERICAS31. The pharmaceutical composition of any one of claims 1 to 25, and 27 to 29, wherein the one or more arachidonic acid ester of high purity has a purity of about 80% or greater, about 85% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, or about 98.5% or greater; wherein embodiments the purity is measured by GC.

32. The pharmaceutical composition of any one of claims 1 to 31, wherein the arachidonic acid of high purity and / or one or more esters thereof of high purity is in an amount of about 75 wt / wt%, about 80 wt / wt%, about 81 wt / wt%, about 82 wt / wt%, about 83 wt / wt%, about 84 wt / wt%, about 85 wt / wt%, about 86 wt / wt%, about 87 wt / wt%, about 88 wt / wt%, about 89 wt / wt%, or about 90 wt / wt%; or from about 80 wt / wt% to about 85 wt / wt%, from about 85 wt / wt% to about 90 wt / wt%, or from about 80 wt / wt% to about 90 wt / wt%.

33. The pharmaceutical composition of any one of claims 1 to 32, wherein the pharmaceutical composition is an oral pharmaceutical composition.

34. The pharmaceutical composition of any one of claims 1 to 33, wherein the pharmaceutical composition is in a capsule, in an embodiment in a hard gelatin capsule, in another embodiment in a soft gelatin capsule.

35. The pharmaceutical composition of any one of claims 1 to 33, wherein the pharmaceutical composition is a liquid, optionally wherein the liquid is in a capsule.

36. A method for alleviating neutropenia resulting from a cytotoxic therapy in a cancer patient, the method comprising: administering a therapeutically effective amount of an arachidonic acid composition or of a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-35 to the patient at least 3 days prior to initiation of the cytotoxic therapy.

37. The method of claim 36, further comprising administering one or more myeloid growth factors to said patient; preferably wherein the one or more said myeloid growth factors is selected from the group consisting of granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF) and interleukin-3.

38. The method of claim 37, wherein the one or more myeloid growth factors is selected from filgrastim, filgrastim-sndz, tbo-filgrastim, pegfilgrastim, pegfilgrastim, lenograstim, argramostim, and molgramostim.

39. The method of any one of claims 36 to 38, wherein the arachidonic acid composition is or comprises arachidonic acid of high purity and / or one or more esters thereof of high purity, and - 68 - 1104747404\8\AMERICASpreferably wherein the arachidonic acid of high purity and / or one or more esters thereof of high purity is arachidonic acid of high purity and / or an ethyl ester thereof of high purity.

40. The method of claim 39, wherein arachidonic acid of high purity and / or one or more esters thereof of high purity is provided as a pharmaceutical composition according to any one of claims 1 to 35.

41. The method of any one of claims 36 to 38, wherein the arachidonic acid composition is or comprises an arachidonic acid glyceride composition.

42. The method of any one of claims 36 to 41, wherein the cytotoxic therapy is chemotherapy.

43. The method of claim 42, wherein the chemotherapy comprises an alkylating agent, an antimetabolite, an anti-tumor antibiotic, a plant alkaloid, a topoisomerase inhibitor, and / or a mitotic inhibitor.

44. The method of claim 43, wherein the alkylating agent is cyclophsophamide, the antimetabolite is 5-fluorouracil (5-FU), the anti-tumor antibiotic or plant alkaloid is doxorubicin, the topoisomerase inhibitor is irinotecan, and the mitotic inhibitor is paclitaxel.

45. The method of claim 43, wherein the chemotherapy comprises a plant alkaloid; preferably wherein the plant alkaloid is doxorubicin.

46. The method of any one of claims 36 to 45, wherein the arachidonic acid composition is administered at least once daily or exactly once daily for at least 3 days prior to initiation of the cytotoxic therapy.

47. The method of any one of claims 36 to 45, wherein the arachidonic acid composition is administered twice daily for at least 3 days prior to initiation of the cytotoxic therapy.

48. The method of any one of claims 36 to 45, wherein the arachidonic acid composition is administered at least one week, at least two weeks, at least three weeks, or at least four weeks prior to receiving the cytotoxic therapy.

49. The method of any one of claims 36 to 45, wherein the arachidonic acid composition is administered at least three days, at least four days, at least five days, at least six days, at least seven days, at least eight days, at least nine days, or at least ten days prior to initiating the cytotoxic therapy.

50. The method of any one of claims 36 to 49, wherein administration of the arachidonic acid composition is continued during the cytotoxic therapy. - 69 - 1104747404\8\AMERICAS51. The method of any one of claims 36 to 50, wherein administration of the arachidonic acid composition is continued subsequent to the cytotoxic therapy.

52. The method of claim 51, wherein administration of the arachidonic acid composition is continued for at least one week, at least two weeks, at least three weeks, or at least four weeks subsequent to the cytotoxic therapy.

53. The method of any one of claims 36 to 52, wherein the therapeutically effective amount of the arachidonic acid composition is at least about 10 mg / kg, at least about 15 mg / kg, at least about 20 mg / kg, at least about 25 mg / kg, at least about 30 mg / kg, at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, or at least about 50 mg / kg per day; preferably wherein the arachidonic acid composition comprises 25% to 100% by weight of arachidonic acid of high purity and / or ester(s) thereof, based on the total weight of the arachidonic acid composition.

54. The method of any of claims 36 to 53, wherein the therapeutically effective amount of the arachidonic acid composition is between about 25 mg / kg and about 100 mg / kg, inclusive; preferably wherein the arachidonic acid composition comprises 25% to 100% by weight of arachidonic acid and / or ester(s) thereof, based on the total weight of the arachidonic acid composition.

55. The method of any one of claims 36 to 54, wherein the arachidonic acid composition is administered orally.

56. The method of any one of claims 36 to 55, wherein the method further comprises alleviating a co-morbidity of neutropenia wherein the co-morbidity is anemia.

57. A method for treating chemotherapy-induced hair loss, the method comprising: administering a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-35 to a patient in need thereof at least 3 days prior to initiation of the chemotherapy.

58. A method for enhancing bone marrow mobilization in donors for stem cell transplant prior to retrieval, for acceleration of bone marrow (in embodiments neutrophil) engraftment in bone marrow transplant recipients, and / or for treatment of genetic neutropenias, (e.g. Severe Congenital Neutropenia (Kostmann Disease)), the method comprising: administering a therapeutically effective amount of an arachidonic acid composition or of the pharmaceutical composition of any one of claims 1-35 to a patient in need thereof. - 70 - 1104747404\8\AMERICAS

Images