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WO2019159185A1 - Compositions et méthodes pour le traitement de l'atrophie d'énergie des protéines - Google Patents

Compositions et méthodes pour le traitement de l'atrophie d'énergie des protéines Download PDF

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WO2019159185A1
WO2019159185A1 PCT/IL2019/050198 IL2019050198W WO2019159185A1 WO 2019159185 A1 WO2019159185 A1 WO 2019159185A1 IL 2019050198 W IL2019050198 W IL 2019050198W WO 2019159185 A1 WO2019159185 A1 WO 2019159185A1
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cbd
thc
composition
administering
cannabis
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Sid TAUBENFELD
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To Pharmaceuticals LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the present invention generally relates to therapeutic products and methods applicable to the prevention and treatment of protein energy wasting (PEW), particularly in patients with chronic kidney disease (CKD) subjected to maintenance hemodialysis (MHD).
  • PEW protein energy wasting
  • CKD chronic kidney disease
  • MHD maintenance hemodialysis
  • CKD chronic kidney disease
  • ESRD end stage renal disease
  • CVD cardiovascular disease
  • MHD maintenance hemodialysis
  • PW protein-energy wasting
  • PEW denotes an inadequate amount of protein and energy intake
  • CKD patients is manifested as gradual and continuing decline in protein and calorie intake that becomes apparent below certain threshold of kidney insufficiency, typically once the glomerular filtration rate (GFR) reaches ⁇ 25-38 mL/min (moderate to severe CKD).
  • GFR glomerular filtration rate
  • the two predominant cannabinoids have been relates to a wide range of clinically beneficial effects, e.g., analgesic, antiemetic, antioxidative, neuroprotective and anti-inflammatory effects, in mammals and humans.
  • W002064109 generally related to pharmaceutical formulations of cannabinoids, including those derived from cannabis plants.
  • W0200801946 described aqueous dronabinol (THC) formulations for wasting syndrome in AIDS.
  • W02015142501 described certain cannabinoid compositions for alleviation of specific symptoms shared by epilepsy, arthrosclerosis Alzheimer's and depression.
  • W02017145160 further related to certain type of cannabinoid compositions with immediate- and sustained- release for the treatment of cancer related cachexia and anorexia syndrome.
  • Kidney failure leads to retention of uremic toxins and various comorbid conditions.
  • Dialytic therapies and various metabolic alterations such as metabolic acidosis lead, particularly in advanced CKD and ESRD, lead to catabolism- inducing effects and thereby to concomitant increase in protein and energy requirements. For example, to maintain a positive nitrogen balance dialysis patients are advised to consume a daily amount of protein as 1.1-1.3 g/kg/day and energy as 35 kcal/kg/day.
  • compositions and products derived from certain cannabis strains can be effective and safe appetite-stimulants in patients under MHD, in which drug intolerance and safety impose significant challenges.
  • One of the important features of the compositions of the invention has been revealed in their specific cannabinoid content or specific ratios between the two main cannabinoids, THC and CBD.
  • THC and CBD cannabinoids
  • medical cannabis improves mood and general wellbeing, and in patients suffering from pain in the context of cancer or multiple sclerosis it was recognized as anxiolytic medication and antidepressant.
  • the effect of THC on the improvement of appetite was documented in conditions such as AIDS, metastatic cancer or Alzheimer’s disease.
  • compositions of the invention are essentially different from the above in terms specific proportions of the two main actives, THC and CBD, and specific amounts and concentrations of said compositions that were effective and safe for improving appetite and nutritional status in patients under MHD, wherein nutritional status and appetite are considered the key predictors of clinical outcomes.
  • compositions of the invention have been demonstrated to impact on self-reported appetite, PEW, nutrition-related markers and markers of inflammation, and over-all nutritional status, and other clinical outcomes closely associated with hospitalization rate and survival, e.g., muscle mass and strength, anthropometric measures, protein catabolism rate, serum albumin levels and health-related quality of life.
  • one drop of Midnight oil (about 0.04 ml) comprises THC and CBD content of about 3% (w/w), and in terms of total amount - about 1.2 mg THC and 1.2 mg CBD, or about 2.5 mg of both cannabinoids; and
  • a high oral dose form wherein one drop of Midnight oil comprises THC and CBD content of about 15% (w/w), and in terms of total amount - about 6 mg THC and 6 mg CBD, or about 12 mg of both cannabinoids.
  • These two oral dose forms have been meticulously evaluated in terms of efficacy and safety as add-on medications to conventional drugs in relation to drug schedule (pre- or post dialysis, or before or after meals), drug dosage (low or high dose forms, single or multiple doses per administration), number of administrations and use of concurrent medications, and other parameters. A detailed description of this clinical trial is provided in Example 1.
  • the trial consisted of two parts: I. - the pharmacokinetic (PK) part for modeling and assessment of the efficacious dosing range, and II. - the nutritional evaluation part for evaluation of treatment outcomes using an extended array of markers. Specifically:
  • the PK part included careful monitoring of drug dosing starting from a low dose (e.g., 1 drop of the 3% oil once a day) and proceeding to a higher dose (e.g., multiple drops of the 3% oil or 1 drop of the 15% oil) while relating to safety and tolerability, and PK data (e.g., THC, CBD or metabolites accumulation between hemodialysis sessions). In absence of adverse events drug dose was increased by 2-fold per administration.
  • the PK part further related to administration schedule (e.g., before or after meals, pre- or post-dialysis).
  • the nutritional evaluation part included an extended array of parameters: VAS (visual analogue scale) and SNAQ (simplified nutritional appetite questionnaire) for appetite assessment; daily energy and protein intake for dietary assessment; EQ-5D and SF-36 for health-related QoL assessment; biochemical nutritional markers (serum albumin, creatinine, transferrin, total lymphocyte count, uric acid, lipid profile, IGF-l), appetite-regulating peptides (leptin, acyl-ghrelin, obestatin, NPY); inflammatory biochemical mediators (CRP, IL-6, and TNF ⁇ ); handgrip strength as functional assessment of muscle mass; anthropometric parameters (body weight, BMI, skinfold thickness, mid arm circumference); lean body mass, % fat mass, fat free mass, phase angle measured by BIA, malnutrition inflammation score, geriatric nutritional risk index and objective score of nutrition on dialysis as quantitative assessment of nutritional status (see Annexes A-D).
  • VAS visual analogue scale
  • compositions derived from certain cannabis strains with approximately equal proportions of THC:CBD (1:1) are effective for improving PEW, immediate appetite perception, and long-term nutritional status in MHD patients.
  • One example of such naturally-based compositions was provided and tested with olive oil extracts of the strain Midnight.
  • Another more recent example is provided with extracts of the strain Mango obeying the ratio of THC:CBD of about 1:1.
  • Still another example of such compositions is currently being tested with extracts of yet another type of cannabis, specifically an CBD enriched strain referred to as 'Avidekel' generally described in US Plant Patent Application 2017/0290286 (a continuation of application No. 14/757, 039, which is a continuation of application No. 14/193, 252).
  • Avidekel encompasses a group of strains produced from the original Avidekel strain further cultivated and enriched for high CBD content, starting from CBD:THC ratio of about 4:1 and more recently reaching an unprecedented ratio of about 20:1.
  • compositions of the invention are expected to include additional naturally occurring actives.
  • the majority of cannabis strains include more than 100 different types of cannabinoids, although at much lesser concentrations than THC and CBD, and also numerous kinds of terpenes.
  • the present invention addresses the specific needs of dialysis patients and provides a targeted therapeutic solution for the problem of PEW in terms of immediate and long-term alleviation and improvement of overall nutritional status.
  • Certain cannabis-based or derived compositions have been shown as effective for improving PEW, immediate appetite perception, and long-term nutritional status in these patients.
  • compositions of the invention were tested in the form of drops of low- and high- concentration oil extracts that are optimal for sublingual administration.
  • a crude dry material of cannabis can be also administered by smoking, inhalation, vaporization.
  • Still another particularly advantageous form of administration especially in the context of MHD is via transdermal route, e.g., in a form of a transdermal patch.
  • compositions and dosage forms of the invention in dialysis patient in a rationalized manner considering various indices of PEW and nutritional status, without risking patient's safety and onset of potential adverse reactions.
  • Figure 1 is a graphic representation of the double-blind placebo-controlled study described in detail in Example 1 (abbreviations are decoded in Annex A).
  • Figure 2 is a graphic representation of various modulators acting in the anorexigenic (dashed line) and orixigenic (solid line) signaling pathways (adapted from Flores A et al. Front Neurosci 2013 Dec 20; 7:256)
  • appetite regulation constitutes an intricate cross-talk between multiple peripheral and central mechanisms, including hypothalamic regulators of appetite at the arcuate and paraventricular axes (Arc/PVN) (see Figure 2).
  • Leptin for example, has opposite effects on Arc neurons in down-regulating neuropeptide Y(NPY) and agouti-related peptide (AgRP), and on pro-opiomelanocortin (POMC) neurons in up-regulating cocaine- amphetamine -related transcripts (CART).
  • Grehlin being released during fasting, also produces opposite effects. Individual outcomes of these signaling cascades are unpredictable, and amount to changes in sensation of hunger and satiety in various degrees in each induvial.
  • peripheral appetite regulators in uremic environment do not correlate with appetite as in the general population mainly due to compensatory counter-regulation (see for example Beberashvili I, et al. Nutr J 2011; 10:68; Borges N, et al.. J Ren Nutr 2014; 24:100-4; Bossola M, et al. J Ren Nutr 2005; 15:244-52; Bossola M, et al. J Ren Nutr 2009; 19:248-55; Mak RH, et al. Kidney Int 2011; 79:697-9; Wright M, et al. Nephrol Dial Transplant 2004; 19(1): 133-140).
  • the invention provides a type of cannabis-based compositions with a particular content of THC and CBD for use in treating PEW and/or improving nutritional status in patients subjected to MHD.
  • the invention provides a type of cannabis-based compositions comprising THC and CBD in approximately equal proportions (about 1:1) for use in treating PEW and/or improving nutritional status in a MHD patient.
  • the invention can provide cannabis-based composition enriched in CBD comprising THC:CBD ratio of about 1:4 up to 1:20 (w/w), respectively.
  • compositions of the invention can comprise THC:CBD ratios of at least about 1:1 and further 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19 or 1:20 (w/w), respectively.
  • the terms 'maintenance hemodialysis (MHD)' or 'chronic MHD' relate to CKD or ESKD patients subjected to hemodialysis in regular intervals.
  • This term herein encompasses a variety of protocols in ter s of duration and frequency of dialysis; and also in terms of adjustment of flow rates of blood and dialysis solutions; sodium, potassium and bicarbonate levels in dialysis solution; and changes accounting for a dialyzer size and patient's weight/ height. This term further refers to short daily home hemodialysis, and nocturnal dialysis.
  • compositions and methods of the invention could also apply to CKD patients who are already manifesting PEW but still abstain from dialysis.
  • PEW' encompasses a wide range of different aspects of malnutrition and metabolic or nutritional aberrations, including inflammation.
  • One way to identify symptoms of PEW is by application of one or more of the following criteria: (1) biochemical measures (serum albumin, transferrin and cholesterol); (2) measures of body mass (body mass index [BMI], unintentional weight loss and total body fat), (3) measures of muscle mass (total muscle mass, mid-arm muscle circumference and creatinine appearance); (4) measures of dietary intake (dietary protein and energy intake) and (5) integrative nutritional scoring systems (subjective global assessment of nutrition and malnutrition-inflammation score).
  • biochemical measures serum albumin, transferrin and cholesterol
  • BMI body mass index
  • muscle mass total muscle mass, mid-arm muscle circumference and creatinine appearance
  • integrative nutritional scoring systems subjective global assessment of nutrition and malnutrition-inflammation score.
  • Nutritional status in the broadest sense is a condition influenced by intake and utilization of nutrients meant to provide macro- and micro-nutrients to maintain body structure and growth, and to sustain energy-requiring processes.
  • nutritional status roughly corresponds to the nutrient intake and assessment of nutrition in (4) and (5).
  • nutritional status proved to be difficult to study, because direct assessment of what and how much person ingests over extended periods of time can be feasible only in small numbers of subjects and under carefully controlled circumstances. To bypass such impracticalities use of surrogate markers of nutrient intake has become wide spread in clinical practice and research studies.
  • the present disclosure teaches the assessment of nutritional status on the basis of comprehensive nutritional scoring systems, such as Malnutrition-Inflammation Score (MIS), Geriatric Nutritional Risk Index (GNRI) and Objective Score of Nutrition on Dialysis (OSND). It also teaches measuring biochemical markers of nutritional status, markers of inflammatory response, appetite-regulating peptides, anthropometric measurements, muscle strength (handgrip), bioelectrical impedance, and also a number of questionnaires for the assessment of appetite and health related quality of life (see Example 1-D).
  • MIS Malnutrition-Inflammation Score
  • GNRI Geriatric Nutritional Risk Index
  • OSND Objective Score of Nutrition on Dialysis
  • the improvement of nutritional status can further comprise an increased appetite.
  • Various methods to assess changes in appetite have been developed, one such method has been presently exemplified by use of the Visual Analogue Scale (VAS) questionnaire (see Annex B).
  • VAS Visual Analogue Scale
  • compositions by virtue of being cannabis- based compositions implies the presence of the two main cannabinoids, THC and CBD, and other active components such as terpenes, flavonoids and other cannabinoids.
  • Tetrahydrocannabinol refers herein to a class of psychoactive cannabinoids characterized by high affinity to CB1 and CB2 receptors, having a molecular formula C21H30O2, an average mass of approximately 314.46 Da, and a general structure of Formula I.
  • Cannabidiol refers herein to a class of non-psychoactive cannabinoids with a low affinity to CB1 and CB2 receptors, having a formula C21H30O2, an average mass of approximately 314.46 Da, and a general structure of Formula II.
  • 'THC' and 'CBD' herein further encompass isomers, derivatives, or precursors of these molecules, such as (-)-trans-A9-tetrahydrocannabinol (A9-THC), A8-THC, and A9-CBD, and further to THC and CBD derived from their respective 2- carboxylic acids (2-COOH), THC-A and CBD-A.
  • A9-THC (-)-trans-A9-tetrahydrocannabinol
  • A8-THC A8-THC
  • A9-CBD 2- carboxylic acids
  • compositions of the invention can comprise THC or CBD of about up to 30%, 25%, 20%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or ⁇ 1% (w/w).
  • compositions comprising THC or CBD in the range of about 30% to 10%, or 10% to 1% (w/w), as high and low dose forms respectively.
  • compositions comprise THC or CBD in the range of about 30%-25%, 25%-20%, 20-15% or 15%-10% as high dose forms, and 10%-8%, 8%-6%, 6%-4%, 4%-2%, 2%-l% or less as low dose forms (w/w).
  • compositions comprise THC or CBD in the range of about 14-16% or about 2-4% (w/w) as high and low dose forms, respectively.
  • compositions can be obtained in a form of an oil extract of a cannabis plant.
  • THC CBD ratio as 1:1 is a rough approximation.
  • the relative content of THC is 8% and CBD is 11% (w/w) yielding a ratio of approximately 3:4.
  • the strain Mango the relative content of THC and CBD is 7% each thus yielding the ratio of 1:1.
  • compositions of the invention are provided with the CBD enriched strains represented by the strain Avidekel.
  • This type of compositions can comprise THC:CBD ratio of about 1:4 up to 1:20, respectively; or in terms of relative THC/CBD content - THC up to 5%, 4%, 3%, 2% or 1.9%, 1.8%, 1.7%, 1.6%.1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1% or less, and CBD up to at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% or more (w/w).
  • compositions of the invention can be adapted for specific administration routes, including enteral (systemic but delivered through the gastrointestinal (GI) tract), parenteral, (systemic but delivered by routes other than the GI tract), topical (local) routes; or in other words, taken via mouth (orally), by injection into a vein (intravenously), into a muscle (intramuscularly), into the space around the spinal cord (intrathecally), topically or beneath the skin (subcutaneously).
  • enteral systemic but delivered through the gastrointestinal (GI) tract
  • parenteral systemic but delivered by routes other than the GI tract
  • topical (local) routes or in other words, taken via mouth (orally), by injection into a vein (intravenously), into a muscle (intramuscularly), into the space around the spinal cord (intrathecally), topically or beneath the skin (subcutaneously).
  • compositions of the invention are oral compositions in the form of solid tablets, capsules, chewable tablets or lozenges to be swallowed whole or sucked on, or consumed as liquids in the form of drops or as add-on to syrups or solutions.
  • compositions of the invention are adapted for a sublingual administration, applicability of such compositions have been presently exemplified.
  • sublingual' encompasses herein sublingual and buccal administrations, wherein sublingual - involves placing the compositions under the tongue and buccal - placing between gums and cheek. In these both administration routes the liver is bypassed, and bioavailability is higher; or in other words, these types of administration have rapid absorption. Sublingual drugs could be particularly advantageous for patients who have trouble swallowing a medication.
  • sublingual and buccal compositions of the invention come in tablets, films or sprays.
  • the latter include, among others, oil extracts employed in the present examples (Example 1-C).
  • compositions of the invention can be adapted for transdermal administration, in the sense of formulations designed to penetrate through the skin layer and exert their effects on deeper or more distant tissues. Utilizing the transdermal route affords minimal first-pass metabolism, eliminates or minimizes comorbidities, adverse drug reactions and side effects resulting in GI, hepatic, renal, or other complications.
  • the compositions of the invention can be incorporated into various transdermal delivery systems by means of known in the art technologies, including first-, second- and more recent third-generation delivery systems. A detailed description of such systems is provided further below.
  • oil extracts are particularly advantageous as they can be easily incorporated into fixed dosage forms (see below), and also into transdermal delivery systems, and transdermal patches.
  • the presently described trial has provided an important insight into the optimal total amount of THC and CBD to achieve the desired therapeutic effect.
  • the oral compositions of the invention can comprise a total amount of both actives, THC and CBD, up to about up to 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 400 mg, 300 mg, 200 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 30 mg, 20 mg, 10 mg or 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg, 1 mg or less.
  • the high dose forms of the oral compositions can comprise a total amount of THC and CBD of up to about 240 mg, 220 mg, 200 mg, 180 mg, 160 mg, 140 mg, 120 mg, 100 mg, 80 mg, 60 mg 180 mg, 120 mg, 60 mg, 50 mg, and the low dose forms - up to about 50 mg, 40 mg, 30 mg, 20 mg, 10 mg and less, or up to about 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg or less of both actives.
  • the low dose forms of the compositions can comprise 48 mg, 36 mg, 24 mg, 12 mg of both actives.
  • composition of the invention can comprise THC and CBD in the range of about 10-15 mg or about 2-3 mg as high and low dose forms respectively. Applicability of this type of composition has been presently exemplified.
  • compositions in the form of transdermal patches can comprise a significantly higher amount of actives.
  • compositions of the invention can comprise one or more additional therapeutic agents.
  • therapeutic agent' encompasses a broad range of drugs routinely used in patients under MHD, including but not limited to: blood pressure tables (anti-hypertensives such as atenolol, amlodipine, doxazosin, and ramipril, losartan and similar), diuretics (furosemide, bumetanide), blood-thinning medications (aspirin, clopidogrel, dipyridamole, warfarin), phosphate binders, alfa-calcidole or cinacalcet (for leveling parathyroid hormone), erythropoietin stimulating agent (for reducing anaemia), iron, tinzaparin (to prevent clotting in dialysis machine), antimicrobial lock (for hemodialysis lines), and other medications (many times including, sodium bicarbonate, allopurinol for gout, quinine
  • compositions of the invention constitute a combination therapy for use in a method of treating and/or maintenance of a patient subjected to MHD with regard to the treatment of treating PEW and improvement of nutritional status and appetite.
  • the term 'combination therapy' encompasses herein a situation wherein a composition of the invention is formulated apart and is administered in succession or simultaneously with another therapeutic agent, and also a situation wherein the composition is formulated together with at last one additional therapeutic agent.
  • compositions of the invention can be applied as monotherapies for the improvement of PEW and nutritional status in patients with a milder CKD.
  • the previously described compositions i.e., the cannabis-based compositions with a particular content of THC and CBD, including oral compositions, compositions incorporated into transdermal delivery systems, and others.
  • said improving of nutritional status further comprises an increased appetite.
  • the methods of the invention can comprise administering to the patient a therapeutically effective amount of a cannabis-based composition comprising THC and CBD in approximately equal proportions (about 1:1), for example compositions derived from the strains Midnight and Mango.
  • the methods of the invention can comprise administering to the patient a therapeutically effective amount of a cannabis-based composition enriched in CBD comprising THC:CBD ratio of about 1:4 up to 1:20 (w/w), respectively, exemplified by compositions derived from the strain Avidekel.
  • the methods of the invention can apply cannabis-based compositions comprising THC:CBD ratios of at least about 1:1 and further 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1: 10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19 or 1:20 (w/w), respectively.
  • Therapeutic dose' or 'therapeutically effective dose' relate to doses of compositions and dosage forms of the invention producing an improvement or treatment of PEW and/or nutritional status in a given patient.
  • the terms 'treating' and 'improving' with respect to nutritional status and PEW are interchangeable.
  • Example 1-D Various methods of measuring an improvement or change in PEW, appetite and nutritional status have been presently exemplified (Example 1-D). Under improvement is meant a change in at least one criteria of PEW or a marker of nutritional status, and also a reduction of up to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more according to relevant clinical score.
  • Plasma albumin Low plasma albumin correlates with body protein stores. Due to its long half-life and large hepatic reserve, it is a relatively advanced manifestation of malnutrition. In some patients under MHD plasma albumin remains low despite supplementation via dialysis.
  • Transferrin level Low transferrin level was linked to co-morbidity in patients under MHD and CAPD (continuous ambulatory peritoneal dialysis).
  • Plasma cholesterol Low plasma cholesterol is characteristic of patients under MHD and is considered a significant predictor of mortality in this group.
  • Plasma creatinine Lower plasma creatinine was closely related to mortality in dialysis patients. Creatinine is produced by a non-enzymatic creatine metabolism in skeletal muscle, and serves for the assessment of lean body mass.
  • TLC Total Lymphocyte count
  • Serum uric acid This marker correlates with most surrogates of body composition, muscle function, inflammation, and health-related quality of life in patients under MHD, and was also related to hospitalizations and risk of CVD death in this group.
  • IGF-l Serum insulin-like growth factor-l
  • Circulating interleukin-6 (IL-6): High circulating IL-6 and its soluble receptor (sIL- 6R) are characteristic of ESKD and dialysis patients. Up-regulated IL-6 was also related to decreased renal function and retention of uremic solutes, volume overload/CHF, persistent infections, oxidative stress, increased visceral fat mass, and other factors related to dialysis (bio-incompatibility, non-sterile dialysate, back-filtration).
  • CRP C -reactive protein
  • TNF ⁇ Tumor necrosis factor alfa
  • Plasma ghrelin Low plasma ghrelin and its acylated form (AG) were associated with mortality, especially in connection with inflammation and other weight-regulating hormones. Presumably, it is the most significant factor contributing to food and energy homeostasis.
  • Plasma ghrelin herein refers to the stomach-derived, 28-amino acid, orexigenic peptide, and also to the two major forms, including an acylated ghrelin (AG) and des-acyl ghrelin (DAG).
  • AG acylated ghrelin
  • DAG des-acyl ghrelin
  • Serum leptin High serum leptin levels are characteristic of patients with renal failure. Leptin has a bimodal function, it down-regulates NPY (a stimulator of food intake), and up- regulates a-MSH (alpha-melanocyte- stimulating hormone - an inhibitor of food intake). Unlike in the general population, leptin was not related to perceived appetite and food intake in dialysis patients. Leptin herein refers to a 16-kDa protein produced by adipocytes.
  • Serum obestatin The role of serum obestatin in dialysis patients is still undecided. High serum obestatin is characteristic of ESKD patients, but more recently its lower levels were associated with mortality in patients under dialysis. Obestatin herein refers to an anorexogenic gut hormone, and specifically to the active form of a 23-amino-acid peptide derived from the C terminal portion of the preproghrelin precursor.
  • NPY Serum neuropeptide Y
  • the methods of the invention comprise measuring at least one marker selected from one or more of the above groups (i) to (iii), i.e., biochemical markers of nutritional status, biochemical markers of inflammatory response or appetite- regulating peptides. Implementation of these markers in the methods of the invention is illustrated in Example D-1.
  • the proposed methods involve an oral administration or sublingual administering of the cannabis-based compositions of the invention.
  • said administering comprises 1 to 3 administrations per day.
  • the methods can involve single oral or sublingual administration per day. This type of methods have been presently exemplified.
  • the methods can also involve multiple daily administrations.
  • the methods of the invention can be applied pre- or post dialysis, as exemplified in Example 1-E2.
  • the methods of the invention can be applied while fasting.
  • the method can be applied with meals or snacks.
  • transdermal administration can involve transdermal administration.
  • Transdermal compositions and dosage forms of the invention will be described in detail below.
  • transdermal route usually involves a prolonged administration over a course of l-3h, 3-6h, 6- l2h, l2-24h or more.
  • the methods of the invention are versatile and can involve oral and transdermal administrations at the same time or in succession in the same patient, depending on patient's preferences and advise of the treating physician.
  • the invention can be articulated as a method for treating PEW and/or improving nutritional status in a patient subjected to MHD, said method comprises:
  • the oral forms or the transdermal patch can be administered alone under specific regimens (daily or nocturnal) pre- or post-dialysis.
  • the oral forms and the patch can be administered in combination simultaneously or in succession under specific regimens (e.g. nocturnal patches) in connection with dialysis (e.g., pre-dialysis oral forms).
  • specific regimens e.g. nocturnal patches
  • dialysis e.g., pre-dialysis oral forms
  • step (a) and (b) are repeated with the administration of increasing doses of the compositions or oral dosage forms, usually by 2-fold, and repeated measurements of marker(s) of nutritional status.
  • Such repetitive titration methods have been exemplified (Example 1-C3).
  • Example 1-C2 the monitoring for adverse events (AE), including those related to cannabis, is of crucial importance.
  • AE adverse events
  • Example 1-C2 The side effects of cannabis overdose are referred to in Example 1-C2, whereby the above method can proceed unless the patient manifests at least symptom of a cannabis-related AE.
  • Example 1-E4 The precise procedure for monitoring for AE in MHD patients is described in Example 1-E4, whereby the above method can proceeds unless the patient manifests at least symptom of AE regardless of causal relationship with the drug.
  • said at least symptom of AE can be classified as a mild, moderate or severe.
  • the above method can further incorporate measuring at least one parameter indicative of dietary intake, appetite and/or health-related quality of life (QoL).
  • QoL quality of life
  • the methods of the invention involve administering of the cannabis-based compositions comprising a content of THC or CBD of about up to 30%, 25%, 20%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or ⁇ 1% (w/w).
  • the methods of the invention apply a therapeutically effective amount of THC or CBD in the range of about 30% to 10%, or 10% to 1% (w/w), as high and low therapeutic doses, respectively. In further embodiments the methods of the invention apply a therapeutically effective amount of THC or CBD in the range of about 14-16% or about 2-4% (w/w) as high and low therapeutic doses, respectively.
  • the methods of the invention can apply a therapeutically effective amount of THC and CBD up to about 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 400 mg, 300 mg, 200 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 30 mg, 20 mg, 10 mg or 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg, 1 mg or less depending on the frequency or number of administrations.
  • both actives are administered in the amount of up to about 240 mg, 180 mg, 120 mg or 60 mg per administration;
  • both actives are administered in the amount of up to about 48 mg, 36 mg, 24 mg orl2 mg per administration.
  • both actives are administered at the therapeutic amounts of about 10-15 mg per administration or about 2-3 mg per administration, as high and low therapeutic doses, respectively. This is particularly true for methods using oral or sublingual routes.
  • transdermal patches can apply a much higher doses of actives with therapeutically effective doses of up to 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg or more.
  • compositions have been provided in the form of oil extracts of certain strains of cannabis. Extracts that are compatible with the presently proposed methods can be obtained from the strains Midnight, Mango and Avidekel
  • the methods of the invention can be provided as combination therapies involving simultaneous administering or in succession at least one additional therapeutic agent for treating or maintenance of the patient subjected to MHD. Relevant therapeutic agents have been discussed above.
  • the invention provides an oral dosage form comprising oil extracts of certain cannabis plants with a particular content of THC/CBD for use in treating or preventing PEW and/or improving nutritional status and/or increasing appetite in patients under MHD.
  • the applicable cannabis plants can be broadly characterized as having THC:CBD ratio of about 1:1, and also CBD enriched strains with THC CBD ratios of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1: 10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19 or 1:20 (w/w), respectively. Examples of such strains are provided with Midnight, Mango and Avidekel.
  • high and low dosage forms of the invention comprising THC or CBD in the range of about 30% to 10%, or 10% to 1% (w/w), respectively.
  • the THC or CBD in these dosage forms is in the range of about 14-16% or about 2-4% (w/w), as high and low forms, respectively.
  • the high dosage forms of the invention can comprise a total amount of THC and CBD up to about 240 mg, 180 mg, 120 mg or 60 mg, and the low dosage forms - up to about 48 mg, 36 mg, 24 mg orl2 mg.
  • the total amount of the THC and CBD in the dosage forms of the invention is in the range of about 10-15 mg or about 2-3 mg, for the high and low forms, respectively.
  • dosage form is used herein in the sense of a pharmaceutical drug product in the form in which it is marketed for use, in terms of specific active and inactive components (excipients), specific configuration (such as a capsule shell, for example), and particular dose (a unit dose).
  • the dosage forms of the invention further comprise buffers and excipients and stabilizing agents.
  • oral dosage forms of the invention can further comprise at least one additional therapeutic agent.
  • the dosage forms of the invention are provided in the form of drops, as in the present clinical trial.
  • dosage forms of the invention can be further encapsulated into hard capsules, uncoated or coated with flavoring and coloring agents, to assist consumption and distinction from other drugs.
  • the dosage forms of the invention can be provided in the form of collagen or gelatin pellets.
  • a transdermal patch As has been noted, of a particular interest is a form of a transdermal patch.
  • the ter s ' transdermal patch ' or ' transdermal delivery system ' (these terms are interchangeable) herein refer to a variety of systems, including first-, second- and more recent third-generation delivery systems known to be particularly advantageous for lipophilic drugs such as cannabis and cannabinoids.
  • the compositions and dosage forms of the invention can be incorporated into these systems using of known in the art technologies,.
  • First-generation transdermal delivery systems essentially refers to the configuration where the drug is stored in a reservoir enclosed on one side with an impermeable backing and on the other side - with an adhesive contacting to the skin.
  • This term encompasses systems wherein the drug is dissolved in a liquid or gel-based reservoir, and also systems where the drug is incorporated into a solid polymer matrix, and also multilayer systems using impermeable, semi-permeable membranes, and systems using liquid chemical enhancers such as ethanol.
  • transdermal systems can employ second-generation delivery systems, i.e., those using chemical enhancers, non-cavitational ultrasound and iontophoresis.
  • transdermal delivery systems are third-generation delivery systems with targeted effects using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound.
  • the dosage forms and compositions of the invention can be incorporated into delivery systems permitting controlled or suspended release of actives.
  • These types of systems have been subject to intensive R&D, yielding advanced delivery systems with so-called 'smart' polymers and hydrogels to make systems that are triggered by changes in environmental factors, such as pFl, temperature, or glucose.
  • the invention provides use of extracts of certain cannabis-plants with a particular content of THC/CBD for the manufacture/ preparation of a medicament for treating PEW and/or improving nutritional status and/or appetite in a patient subjected to MF1D.
  • said use involves cannabis plants comprising THC and CBD in approximately equal proportions (about 1:1).
  • said use can be achieved with cannabis strains such as Midnight or Mango.
  • said use is achieved with oil extracts of the cannabis strains.
  • these types of strains and oil extracts can serve for producing an oral medicament or a transdermal medicaments, including transdermal patches.
  • the terms approximately or about, these ter s herein are interchangeable, denote up to ⁇ 10% deviation from a respective measurement, or 9%, 8%, 7%, 6%, 5% or less a deviation thereof.
  • EXAMPLE 1 Impact of cannabis oil of the invention on nutrition in MHD patients.
  • the following example demonstrates an impact of a cannabis oil of the invention on nutrition in MHD patients with PEW.
  • the example describes a randomized, double-blind, placebo-controlled, parallel-group, pilot study using an extended array of clinical assessment measures and a careful monitoring strategy and design with primary objectives:
  • biochemical nutritional markers (albumin, transferrin, creatinine, cholesterol, uric acid, TLC, IGF-l) in the study population;
  • VAS Visual Analogue Scale
  • MIS Malnutrition-Inflammation Score
  • GNRI Geriatric Nutritional Risk Index
  • OSND Objective Score of Nutrition on Dialysis
  • nPNA normalized protein nitrogen appearance
  • Admission criteria included adult patients with ESKD on 3-times weekly hemodialysis for at least three months prior to screening.
  • Hemodialysis parameters included in all cases: vascular access 4-5h 3-4 times per week at a blood flow rate 250-300 mL/min; bicarbonate dialysate (30 mEq/L) at a dialysis solution flow rate of 500 mL/min; high flux dialyser membrane (biocompatible) with surface area of 1.8-2.2m 2 ; efficiency assessed on the basis of delivered dose of dialysis (Kt/V urea ) using a single-pool urea kinetic model; protein equivalent of nitrogen appearance (nPNA) was calculated from serum urea levels using three-point method.
  • Adverse events (AE) were monitored during the entire (according to ICD-9).
  • MIS Malnutrition-Inflammation Score
  • Midnight oil (investigational product) was made from resin-producing female inflorescences of the Midnight strain and olive oil.
  • the Midnight strain typically contains THC ( ⁇ 9 -THC ) and CBD in a ratio of approximately 1:1 (w/w).
  • the product was analyzed and titrated with pure CBD and olive oil to produce high precision THC/CBD compositions.
  • Each Midnight oil drop (approximately 0.04 ml ) contains about 1.2 mg CBD and 1.2 mg ⁇ 9 -THC for the 3% low-dose oil, and about 6 mg CBD and 6 mg ⁇ 9 -THC for the 15% high-dose oil.
  • Titration period this stage at which each patient attempts to find his/her ideal dose can last for up to 6 weeks and during this time the impact of the treatment on the disease’s symptoms is not as good as when the dose is balanced between maximum impact on the symptoms and minimal side effects.
  • the initial dose is one drop of oil under the tongue three times a day (morning, noon and evening) for three days and then two drops, three times a day, for three more days, and so forth.
  • the dose is increased gradually for each patient depending on the effect of the cannabis oil and tolerability of each patient.
  • the subjects continue titration until AE* is experienced or after reaching the maximum dosage of 20 drops of the low-dose form (3% oil) or 4 drops of the high-dose form (15% oil) per administration. If AE occurs, a patient is tapered down one level to a pre-adverse reaction dose.
  • the first 6 weeks of the titration phase are followed by 10 weeks of relatively stable treatment phase with maximal dose (with no AE) to complete 16 weeks of treatment.
  • Drug interactions The cannabis oil is added to the patient's treatment regime. Cannabis usually works well in combination with other drugs. Four drugs should be avoided: Astemizole, Cisapride, Pimozide, Terfenadine, due to drug interaction.
  • VAS questionnaire in this particular version was developed to assess positive and negative ratings (Flint A, et al. Int J Obes Relat Metab Disord 2000; 24:38-48) of hunger, satiety, fullness, prospective food consumption, desire to eat fatty, salty, etc., (Annex B), and palatability of the test meal (Annex C).
  • SNAP Simplified Nutritional Appetite Questionnaire
  • Short Form 36 quality of life (QoL) scoring system is a version of the health-related QoL scoring system. It is a self-administered questionnaire and was widely used and validated in MHD patients (Kalantar-Zadeh K, et al. J Am Soc Nephrol 2001 ; 12:2797-806).
  • the 8 scales of SF36 are categorized into 2 dimensions: physical health and mental health.
  • EQ-5D is a measure of health status according to EQ-5D descriptive system and EQ visual analogue scale (EQ VAS).
  • the EQ-5D comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, with 3 levels in each dimension. Health status as assessed by the EQ-5D was found as predictive of all-cause mortality in MHD patients (Sexton DJ, et al. Hemodial Int 2016; May 15. doi: 10.111 l/hdi.12415).
  • nPNA normalized protein nitrogen appearance
  • Plasma transferrin, cholesterol, creatinine, uric acid, and TLC are routine measurements using an automatic analyzer.
  • Plasma IL-6 was measured by a commercially available photometric ELISA kit.
  • HGS Handgrip strength
  • MHD Leal VO, et al. Nephrol Dial Transplant 2011; 26: 1354-60. HGS was repeated three times.
  • DIA Bioelectrical impedance analysis
  • Body composition was determined by body impedance analysis (BIA). Impedance is low in lean tissue, where intracellular fluid and electrolytes are primarily contained, but high in fat tissue where fluid contain are very low. Impedance is proportional to body water content (TBW). Lean body mass is calculated from the estimates of TBW. Fat mass is calculated as the difference between body weight and lean body mass . In this study, BIA has been performed at approximately 30 min post-dialysis. The multi-frequency technique (using 3 frequencies: 5, 50 and 100 kHz) was used to estimate TBW, extracellular water (ECW), fat mass (FM) and lean body mass (LBM), using NutriPlus software, version 5.1.
  • ECW extracellular water
  • FM fat mass
  • LBM lean body mass
  • MIS Malnutrition-inflammation score
  • GNRI Geriatric Nutritional Risk Index
  • OSND Objective Score of Nutrition on Dialysis
  • Weight change was determined as the change in edema-free body weight obtained after hemodialysis over the course of 6 months. The lowest score 1 is given if weight loss is 10% or greater. Score 2 indicates weight loss that is between 5% and 10% of dry weight. Score 4 is given for weight loss less than 5% of body weight, or any increase in body weight.
  • Body mass index was also grouped into three categories: BMI less than 17 kg/m2 is scored as 1, BMI between 17 kg/m2 and 19.9 kg/m2 is scored as 2 and normal BMI ( ⁇ 20kg/m2) is scored as 4.
  • Triceps skinfold thickness is scored 1 if it is less than 9.9mm for males and 13.1mm for females. A score of 2 is given if TSF is 10.0-12.4 mm for males and 13.2- 16.4 mm for females; and score 4 is given if TSF above 12.5 mm for males and 16.5 mm for females.
  • MAC Midarm circumference
  • the OSND includes three laboratory values. Flypoalbuminemia less than 3.0 g/dL is scored as 0, serum albumin 3.1-3.4 g/dL is scored as 3 and normoalbuminemia (serum albumin above 3.5 g/dL) is scored as 6.
  • Serum total cholesterol level is scored 0 when it is less than 150 mg/dL; 3, if serum cholesterol is 150-200 mg/dL; and 6 if serum cholesterol is above 200 mg/dL.
  • a cholesterol level less than !30mg/dL (instead of 150 mg/dL) is scored as 0; cholesterol 130-180 mg/dL is scored as 3 in such patients and cholesterol level above 180 mg/dL is scored as 6.
  • Serum transferrin is scored 1 when its level is less than 120 mg/dL; 2, if serum transferrin is 120-149 mg/dL; and 4, if serum transferrin is above 150 mg/dL.
  • Residual Renal Function was estimated by calculating GFR expressed in mL/min/l.73 m 2 (Annex E).
  • GFR was estimated as the mean of urea and creatinine clearance using urine collections made over the entire interdialytic period (48 hours, starting with empty bladder at the start of one dialysis session and ending at the start of the next).
  • the mean blood urea and creatinine plasma concentrations during the collection period were estimated as the mean of the post-FID concentration immediately after dialysis (the study used the slow flow/stop pump sampling technique).
  • the dialysate flow was turned off and the ultrafiltration rate (UFR) was decreased to 50 mL/h, the transmembrane pressure (TMP)/UFR was set to the lowest value or set to zero. Further, the blood flow was decreased to 50 to 100 mL/min for 15 seconds.
  • the mean blood urea and creatinine concentrations during the collection period were estimated as the mean of the post-HD concentration immediately after dialysis (after rebound correction) and the pre-HD value immediately before the following dialysis.
  • RRF were calculated according to the formula recommended by European Best Practice Guidelines for Hemodialysis (European Best Practice Guidelines for Haemodialysis. Nephrol Dial Transplant 2002; 17, Suppl 7:7-9).
  • Cannabis oil was administered in two subsequent time points (herein 'Periods 1 and 2').
  • Period 1 at pre-dose patients was evaluated for a number of clinical parameters, also including PK measurements and monitoring of adverse events (AE) (see Table 3).
  • AE adverse events
  • Dl dosing day 1
  • D2 and D3 dosing day 1
  • 24h and 48h after drug administration were re-evaluated (pre-dialysis) with regard to the same.
  • Period 1 was followed by a washout period (7 days) to allow for complete elimination of cannabis.
  • Dl consisting of a single, 1 drop oral dose of cannabis oil 1.0 ⁇ 0.2 h with pre- and post-dose PK sampling.
  • the drug was administered at post-dialysis after an overnight fast of at least 8 h. Patients were consistently evaluated for a number of parameters, including PK and AE (see Table 3). The same evaluations (pre-dialysis) were repeated on D2 and D3, 24h and 48h. Period 2 was also followed by a washout period.
  • Randomization visit (VI) was the baseline value for the trial, wherein patients were randomly assigned to receive cannabis oil/ placebo. All patients started with a fixed dose decided in the PK part of the study. The study drug was administered after an overnight fast of at least 8 hours, administered orally with meals or snacks.
  • Patients were re-evaluated (pre-dialysis) at VI and at subsequent follow up visits (V2, V3 and V4) with respect to clinical parameters (e.g., physical examination, vital signs, ECG, AE), handgrip strength, and further hematological, biochemical and nutritional markers (e.g., albumin, creatinine, cholesterol, transferring, uric acid, TLC, IGF-l, inflammatory biomarkers (CRP, IL-6, TNF- ⁇ ), appetite-regulating peptides (ghrelin, leptin, obestatin, NPY), and VAS and SNAQ questionnaires for appetite assessment, SF-36 v2 and EQ-5D questionnaires for HRQoL assessment, spKt/Vurea, nPNA have been calculated from blood urea. Additional assessments (post-dialysis) included BIA (within 30 min), nutritional scores (MIS, GNRI, OSND), and drug compliance.
  • clinical parameters e.g., physical examination
  • AEs were recorded at every visit after screening (VI to V4 and follow up VI -V2). Severity of AE was determined by a patient or a physician as a qualitative assessment using the following scale:
  • a drug-related AE is the one meeting at least 3 of the following criteria: (1) following a reasonable temporal sequence from administration of the drug; (2) following a known pattern of response to the drug; (3) could not be reasonably explained by the known characteristics of the patient’s clinical state, environmental or toxic factors, or other modes of therapy administered; (4) decreases on cessation of treatment or reduction in dose.
  • SAEs non-serious or serious
  • An SAE is one that meets any one of the following criteria: results in death; is a life-threatening experience; requires or prolongs inpatient hospitalization (>24 h); causes persistent or significant disability/incapacity.A patient experiencing one or more SAEs were monitored for 60 days after drug discontinuation of the or until AE was determined as no longer significant.
  • At least 50 subjects were screened to give at least 30 subjects randomized (15 cannabis, 15 placebo), and treated for 3 months. Data have been analyzed using SPSS V 17.0.
  • Categorical data was recorded using absolute and relative frequencies (n and %). Continuous data was presented using descriptive statistics (n, mean, standard deviation [SD], minimum and maximum, or median and interquartile range when appropriate. The homogeneity of the treatment groups regarding demographic and baseline characteristics were also assessed.
  • An ANCOVA was applied to changes from baseline to end of treatment taking treatment arm and baseline level into account. The overall test for effect was performed as a two-sided F test with 5% significance. Both treatment groups were compared in the baseline adjusted ANCOVA, and pair-wise t tests - using the Tukey method to adjust for multiple comparisons.
  • the primary efficacy analysis included all randomi ed patients (full analysis set) and was performed according to intention-to-treat principle.
  • Adverse events were evaluated with a Cochran-Mantel-Haenszel ⁇ 2 test for the proportion of patients with the event to test for treatment difference.
  • the intention-to-treat analysis set included all patients who are treated with at least one dose of trial product, the results were presented as change with 95% confidence intervals. In general, model assumptions were checked descriptively using box plots and normal quantile-quantile plots. F.4 PK Analysis
  • Single and multiple-dose PK parameters were derived from the plasma concentration time.
  • a compartmental or non-compartmental PK method were used to analyze the plasma concentrations of cannabis and its metabolites. Individual and mean plasma concentrations at each time point were presented by listings and descriptive summary statistics for each dose group/food condition. Time profile plots of each dose group/food condition, arithmetic and logarithmic means (+SEM) at each time measurement were for plasma data. All PK parameters were presented by individual listings and summary statistics for each dose group/food condition. Box-plots were performed by dose group/food condition for PK parameters. The dose proportionality of PK plasma parameters Cmax and AUC were evaluated using Power model. Log-transformed PK parameters were included in the linear mixed effects model including dose as a fixed effect. Dose proportionality was analyzed using the estimated slope parameter of the linear model. Table 4 below summarizes the main steps in the study.
  • AUC last Area Under the plasma concentration-time Curve from hour 0 to last sample with measurable plasma concentrations
  • IGF-l Insulin-like Growth Factor- 1
  • PreUrea PreCreatspre - dialysis urea and creatinine concentrations in blood sample at the end of collection.

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Abstract

L'invention concerne des approches thérapeutiques pour la prévention et le traitement de l'atrophie d'énergie des protéines (PEW) chez des patients en dialyse d'entretien ou des patients atteints d'une maladie rénale chronique ou en phase terminale. Les produits thérapeutiques et les méthodes de l'invention sont basés sur certaines compositions de cannabinoïdes ayant une accent particulier sur les compositions à base de cannabis, les deux cannabinoïdes principaux, THC et CBD étant présents dans des proportions spécifiques dans des plages définies de concentrations et de quantités.
PCT/IL2019/050198 2018-02-19 2019-02-19 Compositions et méthodes pour le traitement de l'atrophie d'énergie des protéines Ceased WO2019159185A1 (fr)

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