ID#	Category	Author	Date	Title	Type of trial	Participants	Age	Preexisting diseases	Compound	Dose	Summary
1	Blood	Andrioli et al.	1999	Differential effects of dietary supplementation with fish oil or soy lecithin on human platelet adhesion	DB-RCT	60	25-45	Healthy	soy lecithin	25 g/day for 15 days	Platelet adhesion on fibrinogen-coated 96-well microtitre plates was evaluated in the resting condition and after stimulation with 2 microM ADP or 0.02 U/ml thrombin. Compared to the values before the experimental period, the fish oil group showed a significant reduction in stimulated adhesion (with ADP: from 18.8% to 15.6%, p<0.01; with thrombin: from 24.4% to 20.8%, p<0.005), whereas no difference was noted in the resting condition (from 3.6% to 3.5%, NS). In the soy lecithin group, platelet adhesion was increased in all test conditions (with ADP: from 18.7% to 23.2%, p<0.001; with thrombin: from 24.0% to 29.9% p<0.001; resting: from 3.5% to 6.6%, p<0.001). No significant changes were observed in the control group. A good correlation was found between platelet adhesion data and the changes in the platelet fatty acid omega-6/omega-3 ratio caused by the different supplementations. Our results indicate an inhibitory effect of fish oil rich in omega-3 fatty acids on stimulated human platelet adhesiveness and a stimulatory effect of soy lecithin rich in omega-6 fatty acids on resting and stimulated adhesion.
2	CNS	Fujino et al.	2017	Efficacy and Blood Plasmalogen Changes by Oral Administration of Plasmalogen in Patients with Mild Alzheimer's Disease and Mild Cognitive Impairment: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial	DB-RCT	328	60-85	Mild cognitive impairment/early Alzheimer's disease	PL from scallops (jelly-like substance)	1 mg/day orally twice per day for 24 weeks	In an intention-to-treat analysis including both mild AD (20 ≤ MMSE-J ≤ 23) and MCI (24 ≤ MMSE-J ≤ 27), no significant difference was shown between the treatment and placebo groups in the primary and secondary outcomes, with no severe adverse events in either group. In mild AD patients, Wechsler Memory Scale-Revised (WMS-R) improved significantly in the treatment group, and the between-group difference was nearly significant (P = 0.067). WMS-R showed a significant improvement in both groups In a subgroup analysis of mild AD patients, WMS-R significantly improved among females and those aged below 77 years in the treatment group, and the between-group differences were statistically significant in females (P= 0.017) and in those aged below 77 years (P = 0.029). Patients with mild AD showed a significantly greater decrease in plasma PlsPE in the placebo group than in the treatment group no significant efficacy was seen in the MCI group Scallop-derived plasmalogens contain large amounts of DHA and EPA. Some studies suggest that DHA in the form of phospholipids passes through the blood-brain barrier approximately 10 times more efficiently than in the form of free fatty acid.
3	CNS	Watanabe et al.	2020	The Impact of Ascidian (Halocynthia roretzi)- derived Plasmalogen on Cognitive Function in Healthy Humans: A Randomized, Double-blind, Placebo-controlled Trial	DB-RCT	66	45.6	Healthy Japanese with mild forgetfulness	Ascidian plasmalogen oil	one active capsule（200 mg medium-chain triglyceride oil including ascidian plasmalogen oil or placebo capsule（200 mg MCT oil）per day with water, any time during the day for 12 weeks. 1 mg plasmalogen	no adverse events were reported in the current stud the intervention group showed a significant improvement in composite memory score the intervention group exhibited a significant increase in visual memory score after 12 weeks of ingestion compared with the placebo sponsors of the study are supplement makers to measure: https://www.cnsvs.com/WhitePapers/CNSVS-BriefInterpretationGuide.pdf composite memory is a combination of verbal and visual memory
4	CNS	Najima et al.	2016	Improvement in cognitive function by supplement contained plasmalogen for healthy Japanese: A randomized, double-blind, placebo-controlled study	DB-RCT	n=75	57.2 Group A 58.8 Group B 57.0 Group C	Healthy Japanese with mild cognitive problems	P-Solution Inc	soft capsules Subjects in Group A ingested the placebo, subjects in Group B ingested test sample-2 (0.25 mg of plasmalogen), and subjects in Group C ingested test sample- 1 (0.5 mg of plasmalogen) for 12 weeks.	no adverse effects As the primary outcome, the two test groups both showed significant differences in the results of MMSE after 12-week ingestion, compared to Placebo. The results of U-K test, on the other hand, did not show significant differences in any groups. As for the subjective reporting of the cognitive function in the form of a questionnaire, intragroup analysis of the test product showed significant differences in more than half of the items, whereas inter-group analysis between the test group (Test 2) and the Placebo group showed increases differences in 4 to 14 items. In the results of MMSE, significant increases were observed in the intragroup analysis of Test-1 (0.5 mg) and Test-2 (0.25 mg) after 12-week ingestion, respectively Regarding the subjective reporting of the cognitive function using a questionnaire, the intragroup analysis of both Test-1 (0.5 mg) and Test-2 (0,25 mg) showed significant differences in more than half of the items. sponsored by producers of the supplement
5	CNS	Schubert et al.	2011	Milk-based phospholipids increase morning cortisol availability and improve memory in chronically stressed men	DB-RCT	75	30-51	Chronic stress	PL in milk	250 mL of bovine bilk with breakfast 1%, 0.5% or placebo (approx. 300 mg PL/day) for 42 days	funded by supplement producers After receiving PL-enriched milk, both PL groups showed a delayed decline from peak levels in morning salivary cortisol, suggesting a prolonged availability of free cortisol. Treatment with 0.5% PL additionally resulted in a stronger increase of cortisol after awakening, whereas no such differences could be observed in the 1% PL group and the placebo group, respectively. The acute stress response did not significantly differ among placebo and PL groups. An exploratory data analysis further revealed that elderly participants receiving the higher PL dosage had a significant better memory performance after the Trier Social Stress Test as compared with elderly participantsfrom the placebo and low–PL dosage group; no such difference was observed at baseline. Results suggest that PL may increase the availability of cortisol in chronically stressed men and may attenuate stress-induced memory impairments.
6	CNS	Hellhammer et al.	2010	Effects of milk phospholipid on memory and psychological stress response	DB-RCT	46	30-55	healthy	PL (19%)	13.5 g/ day for 21 days	Compared to placebo-exposed individuals, there was a tendency for shorter reaction times in the working memory task, suggesting better performance in PL-treated subjects. The two treatment groups did not significantly differ in their endocrine stress response. However, PL-treated subjects with a higher stress load showed a blunted psychological stress response.
7	CNS	Ylilauri et al.	2019	Associations of dietary choline intake with risk of incident dementia and with cognitive performance: the Kuopio Ischaemic Heart Disease Risk Factor Study	Observational	2497	42-60	Healthy men	Dietary choline assessment	follow up for 21 years	The mean±SD total choline intake was 431±88 mg/d,of which 188±63 mg/d was phosphatidylcholine. During a 21.9-y follow-up, 337 men were diagnosed with dementia. Those in the highest compared with the lowest phosphatidylcholine intake quartile had 28% (95% CI: 1%, 48%;P-trend=0.02 across quartiles) lower multivariable-adjusted risk of incident dementia. Total choline intake had no association with the risk of incident dementia. However, both total choline and phosphatidylcholine intakes were associated with better performance in cognitive tests assessing frontal and temporal lobe functioning. For example, higher intakes were associated with better performance in verbal fluency and memory functions. The APOE phenotype had little or no impact on the associations. Adjustments for the major food sources of phosphatidylcholineonly slightly changed the associations, which indicates thatthese food sources and the other nutrients in these foods fail to explain the inverse association.
8	Diet	Fernandez-Prado et al.	2017	Nutrients Turned into Toxins: Microbiota Modulation of Nutrient Properties in Chronic Kidney Disease	Review	NR	NR	NR	NR	NR	Choline is widely distributed infoods, mostly as phosphatidylcholine in cell membranes and inadequate intake is unusual except in strict vegetarians who consume no milk or eggs. Foods especially rich in choline compounds include egg yolk (800 mg/100 g), kidney and liver (400 mg/100 g), chocolate- and protein-based beverages (300 mg/100 g), salmon and soy protein (200 mg/g), powdered milk (170 mg/100 g) andmeat (150 mg/g)
9	Fatigue	Ellithorpe et al.	2003	Pilot Study: Reduction of Fatigue by Use of a Dietary Supplement Containing Glycophospholipids	Open-label	n=34	50.3	Moderate-severe fatigue	Propax™ with NT Factor®	4 weeks, 3 packets daily (severe), 2 packets daily (moderate) 4 weeks repeat with one pack daily if score was 1-3	Piper Fatigue Scale (PFS) Piper Fatigue Scale score of 6 to 10 were admitted to the study. This corresponded to having high-moderate to severe fatigue (0 = no fatigue, 1-3 = mild fatigue, 4-6 = moderate fatigue, 7-10 = severe fatigue). The average initial fatigue score for the group before treatment was reported as severe (mean score=7.9± 0.82 SD, range=6.4-9.9), after four weeks rated moderate (mean=6.1±1.66 SD, range =2.6-9.5) (p<0.0001), and at eight weeks rated as moderate (mean=4.7±2.01 SD, range=1.5-9.4) (p<0.0001). The Piper Fatigue Scale scores indicated a 33% reduction in fatigue after eight weeks on the supplementation product Summary scores on the PFS showed women improving by 35% and men by 29%.
10	Fatigue	Colodny et al.	2000	Results of a study to evaluate the use of Propax to reduce adverse effects of chemotherapy	Open-label & DB-RCT	n=16 Open-label n=22 crossover DB-RCT	>21	variety of types of cancer	Propax	three times daily in a packet that contained four tablets and one softgel capsule administered with food to limit potential gastrointestinal upset	In the open-label study, patients received the Propax nutritional supplementation five to seven days prior to chemotherapy treatments and continued throughout the next 12 weeks of the chemotherapy regimen After six weeks of chemotherapy, patients crossed over to the other product (placebo to Propax or Propax to placebo). Outcomes were evaluated at baseline, week 6 (mid-point), and week 12 (end of the intervention). In the open-label trial, patients reported significant improvements in fatigue (>0.5 change in score) Patients who began with Propax in the crossover randomized, controlled trial reported improvement in fatigue during the 12-week study period. Patients who began with the placebo experienced improved quality of life; however, fatigue was not specifically mentioned.
11	Fatigue	Nicolson et al.	2010	Lipid Replacement Therapy with a Glycophospholipid-Antioxidant-Vitamin Formulation Significantly Reduces Fatigue Within One Week	Open-label	n=67	57.3	Fatigue	NTFactor® Advanced Physicians Formula with B-Vitamin Complex	five tablets of the glycophos- pholipid supplement containing antioxidants and vitamins daily for one week	The initial PFS group average (mean ± standard error mean) total fatigue score was 9.56 ± 0.36, and after one week of supplement this score improved to 6.02 ± 0.295 or a 36.8% reduction in fatigue. There were no adverse events during the course of the study. The Piper Fatigue Scale can be further dissected into subcategories that include overall fatigue, behavior/severi- ty, affective meaning, sensory and cognitive/mood (Table 3). All of these subcategories showed reductions of 34.6% to 40.6% at the end of the one-week trial, indicating that there were improvements in all subcategories of fatigue
12	Fatigue	Nicolson et al.	2009	DIETARY SUPPLEMENT HEALTHY CURB FOR REDUCING WEIGHT, GIRTH, BODY MASS, APPETITE AND FATIGUE WHILE IMPROVING BLOOD LIPID VALUES WITH NTFactor LIPID REPLACEMENT THERAPY	Open-label	n=30	>18	Chronic fatigue	NTFactor	two months 2 tablets containing 500 mg white kidney bean extract plus 500 mg of NTFactor 30 min before each meal.	The entire group of participants lost an average of 3 pounds (Fig. 1a) with average reductions of 1.5 and 1 inches in hip and waist circumference, respectively (Figs. 2a, 3a). Sixty-three percent of the participants (responder group) lost an average of 6 pounds (Fig. 1b) along with 2.5 and 1.5 inches reduction in hip and waist circumference, respectively (Figs. 2b, 3b), and participants experienced gradual and consistent weight loss along with waist and hip reductions during the entire trial Using the Piper Fatigue Scale the entire test group showed an average of 23% decrease in overall fatigue during the trial Blood lipid profiles generally improved, suggesting improved cardiovascular health, and no adverse effects were noted clinically or found in blood chemistries During the brief trial no adverse effects were reported
13	Fatigue	Nicolson et al.	2012	Lipid Replacement Therapy with a glycophospholipid formulation with NADH and CoQ10 significantly reduces fatigue in intractable chronic fatiguing illnesses and chronic Lyme disease	Open-label	58	55	Fatigue	NT factor COQ10 NADH	2000 mg/serving 35 mg	30.7% reduction in overall fatigue within 60 days analysis of subcategories of fatigue indicated that there were significant improvements in the abil-ity to complete tasks and activities as well as significant improvements in mood and cognitive abilities. Regression analysis of the data indicated that reductions in fatigue were gradual, consistent, and occurred with a high degree of confidence (R2 = 0.960). The data also suggested that further reductions were likely if the participants had continued the supplement beyond the 8-week trial. Males responded slightly better to the combination supplement than females, and the patients with the most severe forms of fatigue responded slightly better than those with milder fatigue, independent of their diagnosis
14	Fatigue & menopausal symptoms	Hirose et al.	2018	Effect of soy lecithin on fatigue and menopausal symptoms in middle-aged women: a randomized, double-blind, placebo-controlled study	DB-RCT	n=96	40-60	fatigue	soy lecithin tablets: phosphatidylcholine, 24%; phosphatidylethanolamine, 20%; and phosphatidylinositol, 12%.	high dose: 1200 mg/day oral low dose: 600 mg/day 8 weeks, six tablets per day after breakfast	In phase I and II clinical trials in patients with cardiovascular diseases, over 5 g of soy phospholipids were administered with no apparent toxicity. Referring to older studies, a daily dosage of as much as 54 g has been administered without any apparent adverse effects. Profile of Mood States (POMS)-brief After 8 weeks of treatment, the mean ± SEM POMS-vigor score was significantly higher in the high dose group than the placebo group (1.9 ± 0.7 vs 0.2 ± 0.6, respectively; P = 0.02 The mean ± SEM diastolic blood pressure (−4.1 ± 1.8 vs 1.2 ± 1.9; P = 0.05, unpaired t-test) and CAVI cardio ankle vascular index (−0.4 ± 0.2 vs 0.07 ± 0.1; P = 0.03, unpaired t-test) significantly decreased after 8 weeks of treatment in the high-dose group compared with the placebo group During the whole study period, no treatment-emergent adverse event was reported by the participants
15	Fatigue/Mitochondrial Function	Agadjanyan et al.	2003	Nutritional Supplement (NT Factor™) Restores Mitochondrial Function and Reduces Moderately Severe Fatigue in Aged Subjects	Open-label	n=20	68.9	Mild-moderate fatigue	NT factor	3 tablets twice daily for 12 weeks	NTF improved the overall fatigue scores of moderately fatigued subjects as measured by the PFS. The initial PFS group average (mean) fatigue score was 5.75±0.6, and after four weeks of NTF this improved to 4.59±0.5 or a 20.2% reduction in fatigue. After eight and 12 weeks of NTF the PFS fatigue scores of the moderately fatigued group improved to 3.8±0.6 (33% reduction) and 3.71±0.65 (35.5%reduction), respectively By sex, the total PFS mean score improved in moderately fatigued subjects after taking NTF for four weeks by 15.3% in women and 23.5% in men. After eight and 12 weeks, fatigue improved in women by 27.5% and 32.3%, respectively, and in men by 40.5% and 42.9%, respectively In contrast to moderately fatigued subjects, however, NTFuse did not have a significant effect on mild fatigue. The improvement in fatigue scores overall after 12 weeks of NTF in mildly fatigued subjects was only 5.6% When subjects stopped using NTF, their fatigue scores increased. Twelve weeks after stopping NTF the moderately fatigued group had fatigue scores of 4.53±0.4 or 21.2% difference with the baseline value, whereas in the mildly fatigued group there were no significant differences in overall PFS fatigue scores Using the PFS subscales the Behavioral/Severity scores improved in moderately fatigued subjects after 12 weeks of NTF an average of 15.3%. The Affective/Meaning subscale improved by an average of 37% and 42.7% after NTF use for 8 and 12 weeks, respectively. Sensory subscale revealed 37.9% and 40.5% average improvements for the group after 8 and 12 weeksNTF use, respectively. Finally, the Cognitive/Mood subscale showed average improvements of 37.2% and 32.9% after 8 and 12 weeks of NTF use, respectively The staining of mitochondria with Rhodamine-123 changed significantly throughout the course of treatment of both moderately and mildly fatigued subjects with NTF Post-hoc analysis with the Bonferroni/Dunn test for specificdifferences between groups indicated that after 8 and 12 weeks of NTF the results were significantly different from baseline (p<0.0001) and after washout for an additional 12 weeks After 12 weeks of NTF the Rhodamine-123 mitochondrial assay yielded results similar to and not significantly different from those found in non-fatigued young adults that had not taken NTF This amounted to an increase in mitochondrial function by 8.4%, 23.8% and 23.7%, respectively, after four, eight and 12 weeks of NTF use in moderately fatigued subjects (Figure1). Some subjects were monitored 12 weeks after discontinuing use of NTF. Although still significantly different from baseline (p<0.001), mitochondrial function returned to intermediate values betweenbaseline and the values at 8 or 12 weeks
16	Gall bladder	Nichitaĭlo & Bulik	2012	Application of essential phospholipids in the treatment and prophylaxis of postcholecystectomy syndrome (article in Russian)	Case series	n=58	NR	Postcholecystectomy syndrome	NR	NR	The drug has hepatoprotective and cholesterol-lowering effects, effectively eliminates pain and dyspeptic symptoms, and normalizes biochemical parameters.
17	Gall bladder	Holan et al.	1979	Effect of Oral Administration of ‘Essential’ Phospholipid, ß-Glycerophosphate, and Linoleic Acid on Biliary Lipids in Patients with Cholelithiasis	Case series	n=6	52	cholelithiasis	EPL	4.5 g/day for 3 weeks	Bile-rich duodenal fluid was obtained prior to the study and following each treatment period. Soybean lecithin feeding effected a qualitative change in biliary lecithin with increased fatty acid unsaturation, but no significant improvement in biliary cholesterol saturation or lipid composition changes including a proportionate increase in biliary phospholipids resulted from any treatment program. A 6-month therapeutic trial with soybean lecithin plus cholic acid failed to show a therapeutic response indicative of gallstone dissolution in the 6 patients. In the chronic therapeutic intervention portion of the study, there were no changes in the size, or apparent number of radiolucent stones and there was no significant change in the ability to concentrate contrast agent.
18	Gallbladder	Vakhrushev & Suchkova	2005	Use of essentiale and cholagogum in prevention of cholelithiasis in fat hepatosis with concomitant cholecystitis (article in Russian)	Open-label	n=100	31-60	fat hepatosis and cholecystitis	essentiale + cholagogum	NR	Changes in physico-chemical properties of hepatic and vesical bile corresponding to stage I of cholelithiasis occurred in most of the examinees. Treatment with essentiale +cholagogum is clinically effective, improves functional condition of bile ducts and the liver, diminishes bile lithogenicity. In fat hepatosis and concomitant cholecystitis, essentiale and cholagogum improve biochemical composition of bile, resulting finally in decreased risk of cholelithogenesis
19	Gallbladder	Vakhrushev et al.	2002	Use of essentiale with cholagogue in fatty liver complicated by cholecystitis for lowering the lithogenic properties of bile	Open-label	n=50	22-60	fat hepatosis and cholecystitis	essentiale + cholagogum	NR	patients were examined by clinical and some modern laboratory ultrasonic, biochemical researches. It was shown that in the most of the patients with fatty hepatosis and an accompanying cholecystitis observes infringement of physical and chemical bile properties what correspond to 1st stage of the disease. The use of Essentiale with Cholagogue in the complex therapy at the pathology of hepato-biliary system renders the expressed therapeutic effect. Thus, alongside with the positive dynamic of clinical disease symptoms the bile lithogenic features are lowering.
20	Gastrointestinal	Lanza et al.	2008	Clinical Trial: comparison of Ibuprofen-PC and ibuprofen on the GI safety and analgesic efficacy in osteoarthritic patients	DB-RCT	n=125	18-83	osteoarthritis	Phosal 35SB + ibuprofen	2400 mg/day ibuprofen + PC fro 6 weeks	The GI related adverse events other than gastroduodenal erosions and ulcers were: dyspepsia (6.3% ibuprofen vs. 14.8% Ibuprofen-PC) and diarrhoea (1.6% ibuprofen vs. 9.8% Ibuprofen-PC), neither of which showed significantly different rates between the two treatment groups The noted Ibuprofen-PC associated diarrhoea and dyspepsia were transient and self resolved, with a median duration of 4.5 and 8.0 days, respectively. Hypertension, which occurred in only 1.6% of the patients taking ibuprofen and 3.3% of the patients taking Ibuprofen-PC Ibuprofen-PC did not change the efficacy of ibuprofen in the treatment of osteoarthritis Pharmacokinetic (PK) analyses revealed that the two study medications had equivalent ibuprofen bioavailability at baseline and Week 4, with regards to Cmax, tmax and AUC Ibuprofen-PC was similar to ibuprofen with regards to both bioavailability and efficacy to treat arthritis symptoms, while reducing the NSAID’s ability to induce gastroduodenal erosions and ulcers In this clinically-relevant subgroup, Ibuprofen treated patients had significantly greater absolute change in Lanza scores and were 3.7 times more likely (or a 270% increased risk) to develop multiple gastroduodenal erosions (Lanza score > 2) than the Ibuprofen-PC treated patients. (>55 y)
21	Gastrointestinal	Karner et al.	2014	First Multicenter Study of Modified Release Phosphatidylcholine “ LT-02 ”in Ulcerative Colitis: A Randomized, Placebo-Controlled Trial in Mesalazine-Refractory Courses	DB-RCT	n=156	~ 40	Ulcerative colitis	LT-02, a newly designed modifi ed release phosphatidylcholine formula,	LT-02 (0.8, 1.6, and 3.2 g) The study medication was provided in sachets with pellets taken orally four times daily.	We found a higher absolute SCCAI (Simple Clinical Colitis Activity Index) reduction in all LT-02 groups compared with placebo The secondary analyses found a remission rate of 31.4 % (11 / 35) in the highest LT-02 dose group compared with 15 % (6 / 40) under placebo The response rates increased from 24 / 40 (60 % ) under placebo to 29 / 35 (83 % ) in the highest LT-02 dose group Th e rate for achievement of mucosal healing was 32.5 % in the placebo group compared with 47.4 % in the pooled LT-02 groups ( P = 0.098, Table 2 ); the rate for histologic healing (histologic index = 1) was 20.0 % in the placebo compared with 35.3 % in the LT-02 groups Symptom resolution occurred ~ 2 weeks earlier and was almost twice as oft en under LT-02 treatment than under placebo treatment Responders of all study arms entered an 8-week follow-up period without study medication. Patients in the LT-02 group were able to avoid relapses over a longer period and in a higher percentage of patients
22	Gastrointestinal x	Cryer et al.	2010	Low-dose aspirin-induced ulceration is attenuated by aspirin-phosphatidylcholine: a randomized clinical trial	SB-RCT	n=204	50-74	Healthy	aspirin or aspirin with PL2200	7 days of oral 325 mg once daily, immediate release aspirin or PL2200.	Overall, 42.2 %of aspirin-treated subjects developed multiple erosions and / or ulcers, whereas 22.2 % treated with PL2200 developed such damage ( P = 0.0027). Gastroduodenal ulcers were observed in 17.6 %of aspirin-treated compared with 5.1 %of subjects treated with PL2200 ( P = 0.0069). PL2200 may be an attractive alternative or complement to proton pump inhibitors in older patients who are at risk of aspirin-induced ulceration.
23	Gestation	Gundermann	2017	Use of Essential Phospholipids (EPL) from Soybean in GESTOSIS	Review (20 clinical studies)	n=1057	NR	Gestoses	EPL	250 mg-1,000 mg of EPL i.v. and/or 900mg-1,800 mg of EPL per os.	Mücke HG reported already in 1963 the successful EPL treatment of 47 patients suffering from severe hyperemesis gravidarum. In 28 women, the symptoms disappeared after 1 injection, in 11 cases after 2 injections, and in the remaining 8 women after 3-4 injections. The ampoules with EPL were administered every other day. No adverse drug reactions (ADRs) were observed. At a later date, Hartel J confirmed these positive results. Nausea and vomiting subsided in a patient with intact intrauterine pregnancy after the 1st EPL injection (250 mg EPL/d) in gestation week 18, after the medication administered before (antiemetics and high dose of vitamin B12) did not show any effect. Further 6 patients with less pronounced symptoms showed the same positive results with EPL. Jaisle F , in contrast, did not achieve relief from symptoms in his patients suffering from hyperemesis gravidarum, even when increasing the dose to 1,000 mg of EPL per infusion per day over 4 days. On the other hand, the EPL infusion led to a decrease of the total lipids (in humans and in animals) within the first few hours after the infusion and a considerable decrease of the urea nitrogen without a significant influence on the total serum protein larger number of patients (n=941) EPL (in combination with basic treatment) was given in the last trimester Fifty- two women with gestosis during the last 3 months of pregnancy (n=22) or shortly before delivery (n=30) received a basic therapy of 500 mg EPL i.v. per day. On average, 7 days of treatment were necessary. In the mean, patients’ edema mobilized 4 days after starting therapy or 3 days after delivery. At the same time, blood pressure as well as urine and diuretic findings became normalized. Symptoms of eclampsia disappeared after 5 days of treatment or 3 days after delivery. Normalization of total lipids, cholesterol, ketone bodies as well as of the liver and kidney function tests was observed within a short period of time. Kovačević M and Gavrić S in 37 patients with primary (n=32) or secondary (n=5) preeclampsia was to eliminate gestosis-induced liver damage by administration of 3-6 capsules (900 mg-1,800 mg) of EPL p.o. for 7 days. After the 7-day treatment total protein increased in more than 90% of the women. A rise in the albumin and γ-globulin levels and a fall in the α2 - and ß-globulin levels were recorded. Except for an elevation of ß-lipoproteins by 15% on average, no changes were observed in lipids. Serum copper values that were already increased at the start of therapy further rose in 60% of the patients. Serum transaminases continued to fall in 50% of the cases within the normal range. The subjective well-being of the women improved quickly, and the drug was very well tolerated Arandelović D and co-workers treated 42 pregnant women with toxicosis, preeclampsia and eclampsia, and prolonged the daily administration of 500 mg EPL i.v. or 1,800 mg EPL p.o. per day to 10-15 days. Additionally, a special diet, symptomatic therapy and 1 tablet of Gestanon (progesterone substitution; 3 × 1/d) were given. As a result of drug treatment, in preeclampsia the symptoms pain, nausea, malaise and insomnia rapidly receded, the occurrence of eclamptic attacks being diminished. Increased blood pressure decreased in most cases, edema and proteinuria disappeared, and kernicterus was not observed. With only 6 stillbirths (5 of them premature births), the infantile mortality rate was lowered to a minimum in cases of toxicosis where treatment was instituted early. No ADRs were reported. De Aloysio D treated 6 patients with 500 mg EPL i.v. in addition to a sedative-hypotensive therapy up to 12 days. Ailamazyan EK treated 38 patients for 10 days with a standard therapy of magnesium, vasodilators, proteins, rheological preparations and Sygethin, and added 500 mg EPL i.v. and 1,800 mg EPL p.o. daily, followed by 1,800 mg EPL p.o. per day until delivery. This EPL-group was compared to 25 patients who received standard treatment only, and to 20 healthy pregnant women. Both authors observed with EPL clear improvements and even normalization of the pathological lipid values Ailamazyan EK noted a significantly higher mean growth of the biparietal diameter of the head of the fetuses due to the additional EPL treatment compared to control, and the newborns presented a significantly higher birth weight, too. According to the author, the penetration of total lipids and triglycerides through the placenta and their utilization by the fetus were increased, thus promoting prevention and treatment of intrauterine fetal hypotrophy. Rendina GM et al. assessed the duration until disappearance of symptoms. They administered 1,000 mg EPL per infusion per day for 10 days to 50 patients with gestosis of different degrees of severity and compared the results to 50 similar cases with toxicosis in pregnancy, which were treated in addition to basis therapy with infusions of glutathione, vitamin B12 and uridine-5-diphosphoglucose. Forty-six patients presented no more symptoms after 10 days of EPL treatment, and the remaining 4 patients after 15 days. In the control group, 40 patients were asymptomatic after 10 days, and the remaining 10 cases after 22 days. No intolerability reactions to the study medication were noted. Ailamazyan EK performed a clinical study with 163 pregnant women with late gestosis of different grades who received EPL (500 mg i.v. and 2,100 mg p.o. per day for 10 days and, until the beginning of labour, 2,100 mg p.o. per day) in addition to basis therapy After delivery, the newborns were administered 50 mg/d - 100 mg/d of EPL i.v. in a 5% glucose solution during the first 7 days. No perinatal death occurred in the EPL-treated group, and the weight at birth was higher. With basis therapy alone the death rate was 5.1%, and hypotrophy of newborns was observed in 8.5%. Blood levels of phospholipids and triglycerides, as well as the values of Diene Conjugates (DC), MDA and SOD in blood and erythrocytes were normalized. Out of 145 pregnant women with late gestosis, allocated according to the severity of nephropathy (mild, moderate, severe), the duration of the disease and the condition of the fetus, 33 patients were treated with EPL. All patients received for 14 days either routine treatment, or they were administered vitamin E and C and/or EPL or Solcoseryl. The dose and way of administration of EPL were not specified. The inclusion of EPL in the comprehensive treatment proved effective in 7 of 8 patients with mild, 13 of 18 with moderately severe and 6 of 7 with severe nephropathy. Discontinuation of the medication led to a relapse within 2-6 days. Alteration of serum lipid peroxidation activity (POL) and considerable reduction of erythrocyte POL activity were associated with restoration of the barrier and membrane function. Compared to the other treatments, the most evident effect on the serum antioxidant activity was exhibited by EPL, manifested by the rise of the level of ceruloplasmin and increased CP/transferring coefficient. No ADRs were reported. Romanenko TG et al. in 2009, who investigated, to what extent EPL can prevent preeclampsia during pregnancy complicated by liver pathology During the 1st course of treatment, increased anemia level and somatic pathology were seen in 30% and 13.3% of the control cases versus 16.6% and 10% under EPL. After the 20th week of pregnancy, the differences became more evident. During treatment with EPL, obstetric complication, such as gestational anemia, decreased from 60% to 30%, placental insufficiency from 36.6% to 16.6%, preeclampsia from 33.3% to 16.6% and primary somatic pathology from 13.3% to 6.6%. As a result, EPL reduced the prevalence of preeclampsia by a factor 2. Out of the patients with pregestosis further development of preeclampsia was registered in 6 of 43 cases (13.9%) but in 13 of 53 cases (24.1%) of the comparison group (P<0.05). The effectiveness of the additional EPL administration was also indicated by a decrease in frequency of delivery complications among the women with liver pathologies: comparing EPL to control, premature breaking of waters was 30% vs. 16.6%, fetal distress 16.6% vs. 6.6%, labour action anomalies 13.3% vs. 6.6%, prevalence of abdominal delivery 16.6% vs. 10%, and frequency of asphyxia in the medium rate from 13.3% to 6.6% and in the severe rate from 6.6% to 3.3% Boris EN et al. investigated in a randomised controlled study the function of EPL against artichoke in the complex treatment of fetoplacental insufficiency of pregnant women with preeclampsia lesions of the hepatobiliary system. Fifty patients got a standard complex treatment (not defined) plus artichoke (dose not defined) and 55 patients 900 mg of orally administered EPL for one month. Both preparations showed clinical efficacy but EPL was more efficient. The clinical recovery indices (especially edema, pain in the right hypochondrium, lack of appetite, stool disorders, skin itching and nausea) were 91.3% for EPL and 83.7% for the medicine that contained artichokes. The same was the case especially for conjugated bilirubin, AST, AP and cholesterol. In total, the efficiency of EPL was 89.5% and for the comparison group 76.8%. Fetal heart rate, condition of the fetoplacental system and biophysical parameters of the fetuses were more improved or normalized under EPL.
24	Hematology	Schneider et al.	1976	Influence of Essential Phospholipids on Human Platelet Aggregability	Open-label	31	49	Hyperlipidemia	EPL	3 g/day orally for 3.5 months	after 8 weeks of treatment, a significant decrease of platelet aggregability was observed, whereas the number of platelets remained unchanged and no alteration of coagulation parameters of fibrinolysis was found
25	Hepatic	Singh & Prasad	1998	A pilot study of polyunsaturated phosphatidyl choline in fulminant and subacute hepatic failure (paper unavailable online)	Phase III Clinical Trial	n=? small	n=?	fulminant/subacute hepatic failure	PPC	350 mg 3x/day 6-8 weeks	in patients of fulminant hepatic failure, recovery period from encephalopathy was faster and mortality rate lower In the patients of subacute hepatic failure, recovery from encephalopathy was faster, mortality rate lower and regression of ascites was significantly higher
26	Hepatic	Dajani et al.	2015	Essential phospholipids as a supportive adjunct in the management of patients with NAFLD	Randomized open-label trial	n=324	21-69	NAFLD	EPL	1800 mg of EPL as 6 capsules per day in 3 doses was given for 24 weeks, followed by 900 mg/day as 3 capsules per day for 48 weeks	42% (135/324) patients reported clinical symptoms before the trial. At the end of treatment, patients reported remarkable improvement of all clinical parameters: both the general symptoms like weakness, asthenia, irritability and sleep disturbances and the non-specific gastrointestinal symptoms like postprandial distress, flatulence, nausea and right upper quadrant discomfort. Only 18.6%, 20.6% and 23.1% of the lone, diabetes mellitus type 2 and hyperlipidemia groups reported clinical symptoms The transaminase levels dropped markedly over the first six months of treatment for the three groups (80.5% of the lone NAFLD patients with a mean drop of ALT of 54.6 IU and of AST of 48.7 IU per patient. In the group of NAFLD with diabetes mellitus type 2 the transaminases behaved similarly in 84.1% of the diabetic patients with a mean drop of ALT of 44.9 IU and AST of 40.5 IU per patient. The same was observed in 87.5% of the NAFLD patients with hyperlipidemia revealing a mean drop of 52.9 IU for ALT and of 49.2 IU for AST per patient. After dose reduction to 900 mg per day there was a slight rise of the transaminases over the next three months but then it steadily decreased and was maintained significantly at a normal level or just above Ultrasound examination indicated a slight but appreciable improvement in the three treatment groups. This occurred in 29.2% of the lone NAFLD patients with six patients becoming normal (5.3%) and 27 patients changing from grade II to grade I fatty infiltration. The diabetic patients had a similar observation with 23.4% of them showing an improvement of the ultrasound findings, four patients (3.7%) attained a normal US and 25 patients changed their echography pattern from grade II to grade I fatty infiltration at the end of treatment. The same trend was noted in 20.2% of the patients with hyperlipidemia who had an improvement of the ultrasound findings with five patients 4.8% becoming normal and 11 patients changing from one grade to a better grade of fatty infiltration. In the lone NAFLD treatment group elastography revealed a change of liver stiffness measurement in 14.2% of the patients with a mean drop of 3.1 K pascal per patient and a range of 0.5–6 K pascal. In the diabetic treatment group however, a change in the liver stiffness occurred in 26.1% of the patients with a mean drop of 3.4 K pascal per patient and a range of 0.3–6.9 K pascal. The patients with hyperlipidemia also revealed a change in the liver stiffness in 20.2% of the patients with a mean drop of 3.1 K pascal per patient and a range of 0.6–5.5 K pascal.
27	Hepatic	Kudinov et al.	2016	Investigation of efficacy of phospholipovit for correction of the hepatic encephalopathy (article in Russian)	Open label trial	n=97	50	Hepatic encephalopathy & chronic alcohol intoxication	Phospholipovit	intravenously in drops at a rate of 2-4 ml/min daily two different daily doses (3.2 and 6.4 g of phospholipid per day) for 5 days volume of infusion was 450 m; chronic alcohol intoxication: course of treatment 10 days, the volume of administration should be reduced to 100-150 ml, 2 times a day	positive cognitive test dynamics (CTI) was observed in 82% of patients who received 3.12 g of phosphatidylcholine (FX). The use of Phospholipovit in the dosage of 6.4 g FX led to the fact that the positive dynamics was observed in all patients who received the drug. In the group of patients who received only standard therapy, positive dynamics of cognitive test (CTI) was observed in 43% of patients. In the group of patients who received 3.2 g FX, in 5 days a decrease in AST activity to 52% of the initial level was observed, i.e. a little more than after standard therapy (up to 60%). However, increasing the dose of FX to 6.4 g allowed for more than a half reduction of AST activity in 5 days compared to the control group - up to 28% of the initial level. Reduction of ALT in the group of patients receiving 3.2 g of FX was up to 30% of the initial level, in the group of patients receiving 6.4 g of FX the reduction was 29%, while in the group of patients receiving only standard therapy in 5 days of treatment there was no reduction of ALT in plasma. the inclusion of Phospholipovit (in a daily dose of 6.4 g FX) led to a more pronounced decrease in the activity of ALT, AST and GHTP compared to the effect of only standard therapy, with a positive trend throughout the treatment. As a result, after 10 days of treatment, the enzyme activity was 35.7% of the initial one.
28	Hepatic	Bruha & Marecek	2000	Essential phospholipids in the treatment of hepatic encephalopathy (article in Czech)	Open label trial	n=12	35-67	Hepatic encephalopathy grade III-IV	Essentiale	2.0 g i.v. daily for 2 weeks	Mean survival in the group treated with Essentiale i.v. was 50.3 days in comparison to 34.7 days in control group. P300 (EEG measurement related to decision making) latencies improved significantly in the Essentiale group in comparison to control group (427.5 ms before vs 366.3 ms after treatment period in the treated group; 346.6 ms before vs 347.5 ms after treatment period in controls). Ammonia level decreased form 95 mumol/l. 5 to 49.7 mumol/l in the treated group, while in controls remained unchanged (46.5 mumol/l before vs 53.5 mumol/l after treatment period). No adverse reactions were observed during the treatment with Essentiale i.v.
29	Hepatic	Pavelkina & Ampleeva	2014	Comparative effectiveness hepatotropic activity remaxol and Essentiale N in chronic viral hepatitis (article in Russian)	Open-label	n=90	NR	Chronic viral hepatitis	EPL	5 ml by i.v., every day for 10 days	Studied hepatotropic activity remaxol and Essentiale N with chronic viral hepatitis (hug) and: 45 patients received the drug remaxol (intravenous drip, 400 ml per day, 10 days), 45 patients Essentiale N (intravenous bolus, 5 ml per day, 10 days). The efficacy was assessed by clinical symptoms, activity ofAlt, AST, bilirubin, alkaline phosphatase, molecules of average weight (MSM), and total effective concentration of albumin (ECA). Remaxol when hug had a hepatotropic effect comparable with Essentiale N, but more effectively cut short asteno vegetative, dyspeptic, cholestatic, and intoxication syndrome, which was confirmed by the significantly low values of MSM and high rates of ECA. The inclusion remaxol in the treatment of patients hug should be considered pathogenetically justified, clinically justified, and promising.
30	Hepatic	Niederau et al.	1998	Polyunsaturated phosphatidyl-choline and interferon alpha for treatment of chronic hepatitis B and C: a multi-center, randomized, double-blind, placebo-controlled trial. Leich Study Group (paper unavailable online)	DB-RCT	n=176	NR	Chronic viral hepatitis	PPC + interferon	1.8 g /day vs. placebo for 24 weeks	A biochemical response (> 50% ALT reduction) was seen in 71% of patients who were treated with PPC, but only in 56% of patients who received placebo. PPC increased the response rate in particular in patients with hepatitis C: 71% of those patients responded in the PPC group versus 51% in the placebo group. Prolonged PPC therapy given to responders beyond the cessation of interferon therapy tended to increase the rate of sustained responders at week 48 in patients with hepatitis C (41% versus 15% in the control group. In contrast, PPC did not alter the biochemical response to interferon in patients with hepatitis B. PPC did not accelerate elimination of HBV-DNA, HBeAg and HCV-RNA. In conclusion, PPC may be recommended in patients with chronic hepatitis C in combination with interferon and after termination of interferon in order to reduce the high relapse rate. PPC may not be recommended for patients with chronic hepatitis B. In contrast to IFN and other antiviral agents PPC does not carry major risks and is tolerated very well.
31	Hepatic	Guan et al.	1995	The effect of polyunsaturated phosphatidyl choline in the treatment of acute viral hepatitis	Randomized open control trial	n=47		Acute viral hepatitis (31 patients had HAV, 12 HBV, 4 non A or B	PPC (Essentiale)	either 300 mg of PPC (Essentiale) orally three times daily or no PPC for 12 weeks.	No side-effects were reported by the PPC-treated patients. Serial serum bilirubin and alanine amino transferase levels were measured up to 12 weeks. The falls in their levels after 2 and 5 weeks, and the lengths of time to their normalization, were not significantly different in the treated group compared to the control group. The results indicated that polyunsaturated phosphatidyl choline had no beneficial effect on the course of acute viral hepatitis.
32	Hepatic	Jenkins et al.	1982	Use of polyunsaturated phosphatidyl choline in HBsAg negative chronic active hepatitis: results of prospective double-blind controlled trial	DB-RCT	n=30	51.4	Chronic active hepatitis	PPC	3 g/day or placebo for one year	A number of patients in both groups reported improved well-being during the trial, 8 of 13 (62%) receiving P.P.C. and 6 of 14 (43 %) in the placebo group Serial assessments revealed no clinical changes in the P.P.C.-treated group. In the placebo group, jaundice and ankle oedema developed in two female patients, associated with a rise in serum aminotransferase levels in both cases (from normal to 860 IUh, respectively) and a 2 cm increase in liver size in one of them At the end of the trial the architectural changes were again similar, but the biopsy score of disease activity was significantly lower in the P.P.C.-treated group Comparison of the initial and final biopsy specimens showed that there was a significant reduction in the biopsy score in the P.P.C.- treated group Furthermore, in three of the P.P.C.-treated patients, but none of the placebo group, the disease was judged to have become inactive (total score less than 2).
33	Hepatic	Hayashi et al.	1999	Beneficial Effect of Salmon Roe Phosphatidylcholine in Chronic Liver Disease	Case series	n=6	67.7	Chronic liver disease (hepatitis or alcohol)	n-3 PUFA rich PCC from Salmon Roe	two capsules after each meal ( about 1600 mg/day of lipids) for six months	The capsules of lipids were well tolerated in all six patients, and no adverse effects were observed during the six-month period of administration There were no significant changes in the serum concentrations of the enzymes related to liver function. Albumin was unchanged, but globulin was significantly reduced for six months. Among lipid metabolism measurements, HDL-cholesterol, apolipoproteins A-1 and E increased significantly The fasting blood glucose levels before and after six-months‘ administration were 141 I95mg/dl (mean I SD) and 152 f 43 mg/dl, respectively, and the HbAlc levels before and after treatment were 6.7 f 1.8% and 7.2 f 2.1%, respectively. There were no significant changes in the haematological measurements during the six months, including the platelet counts, which were 11.7 2 3.5 x 104/n1m3 and 12.2 f 5.3 x 104/mm3 before and after
34	Hepatic	Mukhamedov et al.	2003	Combined therapy of chronic hepatitis C in children with phosphogliv (article in Russian)	Open-label	n=40	children	Chronic hepatitis C	Phospholigv	2 months	The patients were observed for 9 months. An advantage of the combination of phosphogliv, UVIB and referon, providing a stable remission in 36.3% of the patients for 9 months was demonstrated.
35	Hepatic	Lieber et al.	2003	Veterans Affairs Cooperative Study of Polyenylphosphatidylcholine in Alcoholic Liver Disease	DB-RCT	n=789	48.8	alcoholic liver disease	EPL	3 daily chewable tablets, 1.5 g each	The 2-year biopsy was completed in 412 patients. PPC did not differ significantly from placebo in its effect on the main outcome. Alcohol intake was unexpectedly reduced in both groups to approximately 2.5 drinks per day. With this intake, 21.4% advanced at least one stage (22.8% of PPC patients and 20.0% of placebo patients). The hepatitis C virus-positive subgroup exhibited accelerated progression. Improvement in transaminases and bilirubin favoring PPC was seen at some time points in other subgroups (hepatitis C virus-positive drinkers or heavy drinkers). PPC treatment for 2 years did not affect progression of liver fibrosis. A trend in favor of PPC was seen for transaminases and bilirubin (in subgroups). One of five patients progressed even at moderate levels of drinking, and thus health benefits commonly associated with moderate drinking do not necessarily extend to individuals in the early stages of alcoholic liver disease.
36	Hepatic	Akhmedov et al.	2003	Prevention and treatment of postoperative complications of hepatic echinococcosis (article in Russian)	Retrospective analysis	n= 117	NR	liver echinococciasis	Essentiale	NR	The paper presents the outcomes of surgical treatment in 117 patients with complicated liver echinococciasis in the past 9 years. Hepatic function and immunity, their pre- and postoperative changes in the combined use of essentiale and T-activin were studied. It has been found that the functional status of the liver, its detoxifying function in particular, largely impairs and immunosuppression develops in patients with complicated liver echinococciasis. The postoperative combined use of essentiale and T-activin led to the normalization of hepatic function and immunity. The combined treatment reduced the incidence of postoperative complications from 34.83 to 17.2%, such as acute hepatic failure, suppuration of a wound and a residual cavity, isolated abdominal abscesses, pleurisy, and pneumonia.
37	Hepatic	Turecky et al.	2003	Plasma lipid parameters in patients with alcoholic fatty liver after treatment with essential phospholipids	Open-label	n=29	48.9	alcoholic fatty liver	Essentiale forte	3 x 600 mg daily for 3 months	The therapy with essential phospholipids had a positive effect on the subjective symptoms of patients with liver steatosis. The therapeutic effect of the substance on the patient's well-being and the clinical condition was assessed as being good in 23 patients (76%) There was a significant improvement in parameters of hepatocyte integrity (activities of aminotransferases) The activity of ALT was decreased by about 25% and AST by about 33% during the therapy. The activity of gamma-glutamyltransferase (GMT) was also significantly decreased after the therapy. There was no statistically significant change in the plasma level of albumin during the therapy but the albumin concentration of patients with fatty liver before the therapy had not been different from the control group The main plasma lipid parameters total cholesterol and triacylglycerols were significantly higher in patients with fatty liver in comparison to the control group. There was a slight decrease in levels of both investigated parameters during the therapy with essential phospholipids, but this change was not statistically significant. The concentration of HDL-cholesterol of patients before the therapy was significantly higher than that of the control group. There was no statistically significant difference between the levels of HDL-cholesterol before and after the treatment with essential phospholipids. Levels of LDL- cholesterol in the group of patients with fatty liver was slightly higher than in the control group, but this difference was not significant. Similar results were found also for apoprotein A. Plasma levels of apoprotein B were significantly higher in patients with fatty liver than in the control group of healthy individuals (Tab. 2). There was no significant difference in apoprotein B concentration before and after the therapy. There were very good correlations between the levels of apoprotein Aand HDL-cholesterol (r=0.86, p<0.001), and apoprotein B and total cholesterol (r=0.58, p<0.001)
38	Hepatic	Horejsova & Urban	1994	The effect of polyene phosphatidylcholine (Essentiale forte) in the treatment of liver steatosis and ultrasound findings--preliminary study	Open-label	n=30	NR		Essentiale forte, cps. Rhône-Poulenc Rorer Co., contains natural "essential" phospholipids, diglyceride esters of cholinephosphoric acid (enriched with unsaturated fatty acids (linolic, linoleic, oleic) 300 mg, vitamin B1 6 mg, vitamin B2 6 mg, vitamin B6 6 mg, vitamin B12 6 micrograms, nicotinamide 30 mg, vitamin E 6 mg.	Six tablets per day (2 x 3 tablets) were administered for six months.	From the total number of 28 women who completed treatment in 29 % (8 woman) were free from sonographic signs of steatosis and only in 25 % (7 women) the finding remained unaltered. In the remainder the ultrasonic picture improved only partly, in 10 of 11 women (91 %) the non-homogeneity of the parenchyma disappeared, in 3 of 12 women (25 %) the conduction of acoustic signals improved. The authors recorded also regression of hepatomegaly from 12.9 +/- 1.5 cm to 11.4 +/- 1.0 cm (p < 0.0001). There was also a significant decline of laboratory values: ALT from 1.650 +/- 1.612 mu kat/l to 0.812 +/- 0.392 mu kat/l (p < 0.0014), AST from 1.308 +/- 1.341 mu kat/l to 0.613 +/- 0.206 mu kat/l (p < 0.0038), GMT from 2.525 +/- 3.374 mu kat/l to 0.976 +/- 0.727 mu kat/l (p < 0.0078). A statistically significant decline was also found in mean values of total bilirubin (p < 0.0316), cholesterol (p < 0.0129) and triglycerides (p < 0.001). In all patients subjective sensations improved (p < 0.05). The authors provided evidence than in 53.6 % of patients the effect of six-month treatment with Essentiale forte was very good (improvement of all investigated parameters), partial in 42.9 % (improvement of laboratory findings and subjective complaints) ad not quite satisfactory in 3.6 % (only improvement of subjective feelings).
39	Hepatic	Lata et al.	2001	Protective effect of essential phospholipids on liver injury due to total parenteral nutrition (paper not available online)	Open-label	n= 20	NR	total parenteral nutrition due to inflammation of the gut	Essentiale	50 mg every 6 hours i.v., for two weeksas	The baseline results of the mentioned tests did not differ significantly between groups. Bilirubin and AST did not change significantly during the investigation. I n the control group we found, as compared with baseline values, a significantly increase of ALT on the seventh and fourteenth day, a significantly increase of GMT on the seventh and fourteenth day and a slight non-significant rise of ALP on the fourteenth day. In the EPL treated group, as compared with baseline values, a significant rise of ALT occurred on the fourteenth day. We did not observe a significant rise in GMT and ALP. Between the ELP treated and the control group a significant increase of GMT and ALP occurred in the control group, the other values did not differ between groups. Parenteral EPL administration can have a favorable effect on liver damage caused by TPN, associated with cholestasis and biliary sludge. This conclusion can be hypothetically explained by improved bile fluidity and protection of the bile pole of the hepatocyte by essential phospholipids.
40	Hepatic	Tsyrkunov	1992	Lipostabil in the treatment of viral hepatitis B in subjects who abuse alcohol (article in Russian)	Open-label	n= 23	NR	viral hepatitis B, alcoholics	Lipostabil	NR	Lipostabil has advantages as it shortens jaundice, cholestasis, enhances recovery of lipid metabolism in erythrocytic membranes and antioxidant properties of blood.
41	Hepatic	Khodzhaeva	1990	Use of the preparation essential and hemosorption in the complex treatment of chronic alcoholism (article in Russian)	RCT	n=64	NR	chronic alcoholism	essentiale	NR	The results of the treatment of three groups of patients with chronic alcoholism are compared. Group I (n = 26) received essential combined with hemoperfusion, group II (n = 18) placebo combined with hemoperfusion, and group III (n = 20) was on teturam. It has been established that as compared with other treatment measures, essential combined with hemoperfusion contributed to the occurrence of long remissions and the disappearance of somatic complications of alcoholism to a greater degree.
42	Hepatic	Atoba & Olubuyide	1989	The effects of essential phospholipid choline in HBs-Ag negative acute hepatitis (article not available online)	RCT	n=46	NR	Acute hepatitis	EPL, vs. vitamin B control group	6 weeks	Essential phospholipid choline (EPLC) was found to hasten recovery in those with viral hepatitis while the drug showed no added advantage in those with hepatitis due to septicaemia.
43	Hepatic	Maev et al.	2020	Effectiveness of phosphatidylcholine as adjunctive therapy in improving liver function tests in patients with nonalcoholic fatty liver disease and metabolic comorbidities: real-life observational study from Russia	Observational	n= 2827	18–60 years	newly diagnosed NAFLD and who had already been receiving PPC (Essentiale Forte N), which contains 300mg of EPL had a least one of four comorbidities, namely, overweight/obesity, hypertension, type 2 diabetes mellitus, and hypercholesterolemia	polyenylphosphatidylcholine (PPC)	1.8 g /day for 24 weeks	At 24 weeks, there was a significant decrease in liver enzyme levels (all p<0.001 compared with baseline). Across the four comorbidity subgroups, there was a mean drop of ALT levels ranging from 19.7 to 22.0U/L, AST from 16.9 to 18.4U/L, and GGT from 17.2 to 18.7U/L. Similar findings were reported in subgroups with either one, two, three, or four comorbidities, with a significant decrease in liver enzyme levels ranging from 18.4 to 22.4U/L for ALT, 14.8 to 18.7U/L for AST, and 15.5 to 19.5U/L for GGT Essential phospholipids (EPLs) are highly purified phosphatidylcholine fractions extracted from the semen of soybeans, containing linoleic acid and other unsaturated fatty acids.33–35 Polyenylphosphatidylcholine (PPC) is the main active ingredient in EPL Of the 2843 enrolled patients, 2077 (73.1%) were not undergoing any form of lipid-lowering therapy, and 766 (26.9%) reported the use of statins (in 764 patients) or fenofibrate (in 2 patients). Compared with baseline, all lipid parameters were significantly improved at 12 and 24 weeks of the study in patients receiving lipid lowering therapy as well as patients not receiving such therapy
44	Hepatic	Kozlova et al.	2017	Optimization of therapy for hepatobiliary disorders in psoriatic patients (article in Russian)	RCT	n=78	39.87	medium-severe psoriasis with liver disease	Phosphogliv	2 capsules 3 times/day for 24 weeks	Ursosan was more effective in the therapy of NAFLD and gallbladder abnormality in patients with progressive psoriasis than phosphogliv
45	Hepatic	Otegbayo et al.	2012	Livolin ameliorates elevations in alanine transaminase in HIV infected patients commencing highly active antiretroviral therapy	Open-label	n=100	NR	HAART induced hepatotoxicity	Livolin forte	1 capsule three times daily in addition to their HAART	significant decrease in the mean ALT levels of the Livolin supplemented group who had baseline levels above the reference range. This was not observed in the unsupplemented group
46	Hepatic	Watanabe et al.	1988	Multimodal treatment resulting in rapid improvement of fatty liver in obese patients	Open-label	n=12	46	obese patients with liver disease	EPL	500 mg, 3x /day for 2 months EPL vs. 500 mg 3x/day nicotinic acid orally	decreased TC and TG decreased fat in the liver as seen in CT no adverse effects ALT, glucose tolerance, obesity index and skin fold thickness improved in both groups efficacy was similar in both groups, side effect of flushing occurred in the nicotinic acid group
47	Hepatic	Koga et al.	1991	Clinical progress of 51 fatty liver cases analyzed by liver function tests and ultrasonic screening and results of EPL administered cases	Case series	n=51	42.6	obese, diabetic, alcoholic with FLD	EPL	500 mg 3 times per day for 6 months orally	All cases included: US improved or normalized in 51% of patients (P,0.001); AST (P ns), ALT, and y-GT ↓ in males (P,0.01). Improvement in LFT in 72% of patients. Alcohol-excluded evaluation: US improved or normalized (P,0.01); AST, ALT, and y-GT improved or normalized (P,0.01, P,0.001, and P,0.05, respectively). No further improvement after 16 weeks. Subjective symptoms improved or disappeared.
48	Hepatic	Knauff et al.	1993	Der Einfluß von Cholinphospholipiden auf das Spektrum der freien Plasmaaminosäuren bei toxischen Leberschäden)	DB-RCT	n=20	NR	alcohol damage	NR	NR	normalization of raised serum levels of ALT, AST, GGT, AP, LAP, LDH, bilirubin, decreased IgA
49	Hepatic	Schüller et al.	1985	Placebo-controlled study with polyunsaturated phosphatidylcholine in alcoholic steatosis of the liver (article in German)	RCT	n=40	NR	alcohol	NR	NR	decrease in ESR, AST, ALT, GGT
50	Hepatic	Salvioli et al.	1977	Lipid Substrates for LCAT Activity in Liver Disease	Case-control	8 healthy 6 cholestasis 10 cirrhosis	NR	Cirrhosis	Polyunsaturated phosphatidylcholine (PU-PC)	single intravenous infusion of 3g	changes in RBC related to hemolytic anemia regressed the ratio of chol/phosopholipid returned to normal proportion of unsaturated fatty acids in the membrane phospholipids rose significantly In normal subjects, no statistically significant differences of the enzyme activity levels were observed before PU-PC infusion. There was a tendency to lower LCAT activity in patients with liver disease compared with normal subjects before PU-PC infusion. After PU-PC infusion a significant increase of LCAT activity was observed with methods 2) and 3) in patients with cholestasis (32, 8/47.2 and 30.4/5 I.lpM/l/h) and with method 3 in patients with cirrhosis (20.3/34.6pM/l/h). Gas chromatographic analysis of HDL-phosphatidylcholine and HDL-cholesterol revealed a 'low content of polyunsaturated fatty acids in patients with liver disease as compared to normals. Treatment by PU-PC infusion yielded an increased content particularly of linoleic acid in these high-density lipoprotein lipids.
51	Hepatic	Gonciarz et al.	1988	Randomised placebo-controlled double blind trial on 'essential' phospholipids in the treatment of fatty liver associated with diabetes	RCT	30	54	Diabetic fatty liver	Essentiale forte	1.8 g/day for 182 days 2x300mg 3x per day immediately before meals	All obese patients were instructed to reduce diet (ca 1200 kcal/day) containing 1 gm per kg protein liver size was significantly decreased in the treated group GGT decreased in the treated group histology was improved in 8 participants in the treated group and only 1 in the placebo group sense of well-being was improved in 8/15 of the treated group and only 1 of the placebo group
52	Hepatic	Hisanaga	1980	Abnormality of Liver Function in Patients Treated with Antiepileptic Drug and a Trial of Polyene Phosphatidyl Choline Treatment for These Patients	Open-label	38	NR	Repair of drug-related liver injury	PC	1-15 months (average 5.9)	drug levels were not affected by treatment the higher the initial GGT, the greater the effect of treatment conclusion that it is reasonable to give PPC with AED in order ot protect the liver function
53	Hepatic	Dajani & Popovic	2020	Essential phospholipids for nonalcoholic fatty liver disease associated with metabolic syndrome: A systematic review and network meta-analysis	SR 10 studies	22-324	NR	NAFLD	EPL	4-72 weeks	In the direct meta-analysis (four randomized controlled trials), compared with antidiabetic therapy alone, EPL plus antidiabetic therapy was associated with a significantly greater reduction in [alanine aminotransferase (ALT); MD: 11.28 U/L (95%CI: -17.33, -5.23),P = 0.0003], triglyceride [MD: -49.33 mg/dL (95%CI: -66.43, -32.23),P < 0.0001] and total cholesterol levels [MD: -29.74 mg/dL (95%CI: -38.02, -21.45),P < 0.0001]. There was also a significant increase in the rate of overall improvement [relative risk 1.50 (95%CI: 1.26-1.79),P < 0.0001], and risk of no disease (P = 0.0091), and a reduction in moderate disease (P = 0.0187); there were no significant differences in severe disease, mild disease, or significant improvement. In the cohort meta-analysis of three non-randomized clinical trials, the MD in ALT levels was -16.71 U/L (95%CI: -24.94, -8.49) and 23% of patients had improved disease. In the cohort meta-analysis of five randomized trials, MD in ALT levels was –28.53 U/L (95%CI: -35.42, -21.65), and 87% (95%CI: 81%, 93%) and 58% (95%CI: 46%, 70%) of patients showed clinical improvement and significant clinical improvement.
54	Hepatic	Ivashkin et al.	2021	Correlation of Objective Endpoints and Subjective Patient‑Reported Outcomes in NAFLD Treatment with Essential Phospholipids: Real‑World Data Based on Pooled Analysis of Observational Studies	Meta-analysis of Observational Studies	data pooled from 3 studies 3384	51 54 54	NAFLD	Essentiale forte 1800 mg/day	at least 12 weeks	A total of 82.2% of patients were adherent to 12 weeks of EPL treatment high/very high satisfaction was reported by 15.3%/65.9% of clinicians and 15.9%/64.4% of patients. There was positive correlation between patients’ adherence and satisfaction and significant improvement in laboratory (transaminases, lipid profile; p < 0.001) and ultrasound (steatosis, p < 0.001) parameters, and improvement in symptoms (p < 0.001) after 24 weeks of EPL. Male patients, patients with unhealthy lifestyles, and those with more comorbidities showed a better response in laboratory and ultrasound parameters Only 0.3% of patients (n = 11) reported premature termination of treatment; the main reasons for treatment discontinuation were improvement of well-being (n = 5), patient’s decision (n = 1), exacerbation of chronic concomitant disease (n = 1), pancreatic fluid collection (n = 1), and unknown (n = 3) Overall, patients who were adherent to 24 ± 1 weeks of EPL treatment showed significant decreases in fasting glucose, glycated hemoglobin (HbA1c), total cholesterol, very low-density lipoprotein (VLDL), and total bilirubin compared with patients who were not treatment adherent and had less pronounced changes in these parameters impossible to fully distinguish the effect of EPLs from the effects of weight loss and physical activity
55	Interactions	NR	NR	www.webmd.com	article	NR	NR	NR	PC	NR	Drying medications (Anticholinergic drugs) interacts with PHOSPHATIDYLCHOLINE Some drying medications are called anticholinergic drugs. Phosphatidylcholine might increase chemicals that can decrease the effects of these drying medications. Some drying medications include atropine, scopolamine, and some medications used for allergies (antihistamines) and for depression (antidepressants). Medications for Alzheimer's disease (Acetylcholinesterase (AChE) inhibitors) interacts with PHOSPHATIDYLCHOLINE Phosphatidylcholine might increase a chemical in the body called acetylcholine. Medications for Alzheimer's called acetylcholinesterase inhibitors also increase the chemical acetylcholine. Taking phosphatidylcholine along with medications for Alzheimer's disease might increase effects and side effects of medications for Alzheimer's disease. Some medications called acetylcholinesterase inhibitors include donepezil (Aricept), tacrine (Cognex), rivastigmine (Exelon), and galantamine (Reminyl, Razadyne). Various medications used for glaucoma, Alzheimer's disease, and other conditions (Cholinergic drugs) interacts with PHOSPHATIDYLCHOLINE Phosphatidylcholine might increase a chemical in the body called acetylcholine. This chemical is similar to some medications used for glaucoma, Alzheimer's disease, and other conditions. Taking phosphatidylcholine with these medications might increase the chance of side effects. Some of these medications used for glaucoma, Alzheimer's disease, and other conditions include pilocarpine (Pilocar and others), and others.
56	Kidney	Gapon	1990	The effect of cholagogic preparations and Essentiale on the natriuretic hormone content of the blood plasma and on kidney function in patients with liver pathology	Case series	n=41	NR	chronic opisthorchiasis	Essentiale	NR	The effect of cholagogic drugs on blood plasma content of natriuretic hormone (NH) in 41 patients with chronic opisthorchiasis was studied. The drugs were found to exert no effect on NH content and the kidney function in this pathology. The use of essentiale in patients with persistent hepatitis and cirrhosis of the liver was shown to increase sodium excretion due to an increase of NH content.
57	Lipids	Dobiásová et al.	1988	Effect of polyenoic phospholipid therapy on lecithin cholesterol acyltransferase activity in the human serum	Open-label	n=18	NR	chronic glomerular nephritis & hyperlipidemia	NR	effects evaluated after 2 months of treatment and again 3 months later	An immediate effect of the treatment was reflected in a significant increase in the fractional esterification rate (FER % .h-1) and a marked reduction of the concentration of triglycerides (TG). Discontinuation of the drug resulted in the return of TG and FER values to the initial levels and in a rise of total (TCH) and unesterified cholesterol (UCH), HDL-cholesterol (HDL-TCH) and the molar esterification rate (MER mumol.1-1.h-1). The activity of LCAT estimated by radioassay in common and endogenous substrates varied in parallel.
58	Lipids	Simons et al.	1977	Treatment of hypercholesterolaemia with oral lecithin	Open-label	n=10	NR	3 healthy, 7 hyperlipidemic	Lecithin granules	4.5 g per day in three divided doses. After several weeks, dosage was increased to between 20 and 30 g per day (delivered by measuring cup). Several subjects had a second control period (approximately 4-6 weeks), followed by further treatment with lecithin and/or lecithin 30 g plus clofibrate 2 g. 8 weeks to 11 months	Lecithin alone produced statistically significant reductions in plasma cholesterol concentration in one out of three normal subjects and in three out of seven patients with hyper- cholesterolaemia. In 4/10 subjects, lecithin therapy led to a significant fall in plasma cholesterol concentration (10-18%). Plasma triglyceride concentrations showed no significant change during lecithin therapy alone, except in subject 8. In the four subjects showing a significant reduction in plasma cholesterol concentration, this was almost totally accounted for by a reduction in LDL or beta lipoprotein cholesterol. Their mean (+1 SD) LDL cholesterol pre- treatment was 8 mmol/l and this became 6 mmol/l on maximal doses There were no significant changes in VLDL or HDL Lecithin was well tolerated by all subjects without adverse side effects temporary weight gain of about 1 kg at the commencement of therapy but this rapidly stabilised. However, subject 8 gained about 6 kg over the whole period.
59	Lipids	Thompson et al.	1976	Effects of Intravenous Phospholipid on Low Density Lipoprotein Turnover in Man	Open-label	n= 8	21-43	Healthy	Intralipid (10%) or Egg Lecithin	intragastric, i.v.	LDL cholesterol and protein concentrations remained stable during both phases of the study in both the control and intragastric Intralipid groups In contrast there were significant increases in both LDL cholesterol and protein during phase (b) in the group given intravenous Intralipid. Similar rises occurred in the 2 subjects who received intravenous egg phospholipid The plasma half-life, and the absolute and fractional catabolic rates of LDL protein (apo-LDL) were unaffected by intragastric Intralipid, whereas apo-LDL half-life was prolonged and its fractional catabolic rate was decreased by intravenous Intralipid. Similar changes were observed after intravenous administration of the egg phospholipid constituent of Intralipid. Accompanying increases in the oleate: linoleate ratio of both high and low density lipoprotein cholesterol esters were secondary to phospholipid exchange between infused and endogenous lecithin. These results suggest that the increased concentration of LDL in plasma following intravenous administration of egg phospholipid-containing emulsions was due, at least in part, to a decrease in the fractional catabolic rate of apo-LDL. The data further suggest a possible relationship between apo-LDL catabolism and the fatty acid composition of LDL
60	Lipids	Klimov et al.	1995	"'Essential" Phospholipids Versus Nicotinic Acid in the Treatment of Patients with Type lIb Hyperlipoproteinemia and Ischemic Heart Disease	Open-label	n= 100	51.2	Hyperlipoproteinemia Type 2b, Ischemic heart disease	Lipostabil	2 ampules of 5 ml i.v. per day for 2 weeks and then 1.8 g/day oral Lipostabil 300 Forte for 5.5 months Other group was given 1.5 NA	Lipostabil is a highly purified phospholipid fraction extracted from soybean and containing PC as an active ingredient, with polyunsaturated fatty acids as acyl residues in teh 1-and 2-positions of the PC molecule. EPL EPL is incorporated into different lipoprotein particles and, due to its unsaturated nature, which differs from human PC, it is capable of modifying lipoprotein properties, thus leading to a lipid-lowering effect no side effects in the Lipostabil group whereas 8 participants dropped out of the trial in the NA group due to adverse effects angina attacks were reduced in intensity and number by a similar extent in both groups Lipostabil group led to an increase in physical tolerance After 6 months, both groups showed reductions of TC, LDL-C and TG Niotinic acid showed greater effects in the reduction of TG A subgroup analysis showed a favourable shift of HDL subtypes to the most antiatherogenic HDL2b in the Lipostabil group
61	Lipids	Spann	1987	Effects of Equal Amounts of Linoleic Acid in Orally Supplied Polyenylphosphatidylcholine or in Safloroil on Plasma Lipoproteins	Open-label trial	n=8	25-35	Healthy subjects (males)	PPC in the form of a paste	polyenylphosphatidylcholine in a dosage of 10 g per day 3 weeks compared with an equimotar amount of linoleic acid in 7 g safloroit per day	Phospholipid concentrations increased significantly with polyenylphosphatidylcholine in VLDL. Apolipoprotein B in LDL was significantly decreased by both substances. Apolipoprotein A-I and A-II in HDL increased significantly with polyenylphosphatidylcholine. With safloroil this effect was limited to apolipoprotein A-I, but less impressive. The effects of both substances are comparable in the decrease of apolipoprotein B and probably cholesterol. A special effect of polyenylphosphatidylcholine was observed on phospholipids in VLDL and on apolipoprotein A-I and A-II in HDL.
62	Lipids	Wojcicki et al.	1995	Clinical Evaluation of Lecithin as a Lipid-lowering Agent	Open-label	n=32	44	primary hyperlipidemia	Lecithin granulate (Sternpur)	orally (1 teaspoon: -3.5 g), three times a day before meals for 30 days (Sternpur contains some 73% phospholipids and approximately 23% of other important active ingredients)	Mean total cholesterol concentration was significantly decreased by 33%, while LDL-level was diminished by 38%. HDL-cholesterol concentration at the same time was increased significantly by 46%. Mean triglyceride concentration in these persons was significantly decreased by 33%. In conclusion, lecithin, a preparation obtained from soya, should be administered for the prevention and treatment of atherosclerosis
63	Lipids	Knuiman et al.	1989	Lecithin Intake and Serum Cholesterol	Systematic review	24 trials	NR	NR	Lecithin	oral	A systematic review of 24 studies that analyzed the effect of oral lecithin on serum cholesterol reported that only the early studies reported marked reductions of serum choelsterol. Most investigators noted only small changes or none at all of the 4 studies that controlled for lecithin effect compared to fatty acids, none showed a benefit and two studies found vegetable oils were superior
64	Lipids	Burgess et al.	2005	Phosphatidylinositol increases HDL-C levels in humans	randomized open-label	16	NR	normolipidemic	Phosphatidylinositol	oral 2.8 or 5.6 g/day for 2 weeks	PI was well tolerated by all subjects. PI significantly affected the levels of HDL-C and triglyceride in the plasma of subjects receiving PI with food. The lower dose showed a 13% increase in HDL-C, whereas the high dose showed an increase of 18% over the 2 week period. Both low- and high-dose groups showed significant increases in plasma apolipo-protein A-I. The high dose of PI also decreased plasma triglycerides by 36% in the fed subjects. These data suggest that after only 2 weeks, PI may have a comparable therapeutic value to niacin, with negligible side effects
65	Lipids	Schneider et al.	1979	Effect of polyenyl phosphatidylcholine on clofibrate-induced increase in LDL cholesterol	DB-RCT cross-over	n=67	57.2	Primary hyperlipoproteinemia Type 2 or 4	PPC	1.2 g clofibrate AND 1.8 g of PPC for 4 weeks capsules	Total cholesterol was lowered significantly (2 p < 0.01) by the combination, and there was a trend (2 p < 0.1) under clofibrate. Triglyceride levels were very significantly reduced (2 p < 0.001) by the combination and by clofibrate. Phospholipids were also reduced in both instances. The reduction in serum phospholipids was significant (2 p < 0.05) after treatment with PPC + clofibrate, but it was not significant after clofibrate alone there was a marked increase in triglycerides during the placebo period, There was a clear absolute increase in LDL cholesterol after clofibrate treatment, but there was a very small absolute decrease after treatment with the combination of PPC plus clofibrate From this point of view, the combination of PPC + clofibrate appears to be a more favourable therapeutic principle than clofibrate alone.
66	Liver	Butov et al.	2014	Essential phospholipids in the treatment of alcohol-related liver disease: clinical and experimental study (article in Russian)	Open-label	NR	NR	Alcoholic liver disease	EPL	NR	The application of essential phospholipids reduces the morphological severity of inflammatory and degenerative changes in the liver, improves the clinical picture and laboratory status of patients.
67	Liver	Sas et al.	2012	Beneficial Influence of Polyunsaturated Phosphatidylcholine Enhances Functional Liver Condition and Liver Structure in Patients with Nonalchoholic Steatohepatitis	DB-RCT	n=215	NR	Diabetic patients with NASH	Essentiale forte N	1368 mg PC + in addition to metformin and dietary advice	follow up over 7 years A significant reduction of all the liver enzymes was observed after treatment by PUPC, viz. baseline vs. six months after treatment: ALT: 56.5±28.6 IU/L vs. 35.2±18.4 IU/L, p = 0.02,AST: 39.0±9.0 IU/L vs. 26.5±7.2 IU/L, p = 0.04, GGT: 38.2±11.4 IU/Lvs. 27.5±8.6 IU/L, p = 0.03). Ultrasound studies were performed on the basis of liver attenuation value assessment and revealed the hepatic echo-texture had become significantly improved after PUPC treatment in 101/152 (66.4%) of patients (p = 0.02), while there was no change in 7/152 (4.6%) individuals. I n the group of patients LIG further dynamics of the liver enzymes had no statistically significant differences from CG, but sonographics signs of fatty liver statistically decreased in 93/114 (81.6%) and became more effective control of diabetes in 98/114 (86.0%) patients (significant reduction in HBc). The results of liver biopsy (histological examination) andFibromax test showed, that in patients with NAFLD additionally treated by PUPC, the progress of hepatic fibrosis was significantly slowly, then in CG (Fibromax test result: F2 vs. F3) (p = 0.03). In addition after of treatment we found significant increase of steatosis in long-term CG, and its reduction in LIG (p = 0.02)
68	Liver/Metabolic	Babak & Bashkirova	2019	Results of Correction of the Hepatic Steatosis on the Background of Hypertension and Overweight with Help of Essential Phospholipid Complex	Open-label	n=52	NR	Hypertension, obesity	EPL	2 capsules, 3x/day for 6 months	the index of hepatic steatosis significantly decreased after 6 months the analysis of lipidogram parameters also showed some improvements in the form of decreasing total cholesterol, TG, and increasing HDL - however, the parameters didn't normalize weight loss did not occur the system excluded anthropometric parameters, dietary regimen, and alcohol consumption from the analysis, despite significant changes in these parameters during treatment
69	Metabolic	Bobkova et al.	1989	Metabolic effect of lipostabil-forte (article in Russian)	Open-label	n=30	NR	Coronary Heart Disease	lipostabil-forte	NR	Effects of lipostabil-forte containing unsaturated fatty acids on serum lipid concentrations, plasma and erythrocyte lipid and phospholipid fractions, immunoreactive insulin and thyroidal hormone levels were studied During the therapy of all the patients within 1 month and occasionally 3 and 6 months, there was a statistically significant reduction in serum triglycerides, an increase in relative erythrocyte phospholipid levels, and in plasma and erythrocyte phosphatidylcholine, as well as a reversal of hyperinsulinemia and improvement of thyroid function.
70	Metabolic	Almazov et al.	1986	Use of lipostabil to correct lipid metabolism disorders in patients with ischemic heart disease (article in Russian)	in vitro method for testing effects of lipostabil	NR	NR	Ischemic Heart Disease	Lipostabil	NR	A comparative study of biochemical and immunologic patterns showed lipostabil treatment to be effective in less than half of the patients with unstable angina. A method is developed for in vitro testing of individual blood mononuclear sensitivity to lipostabil effects. The proposed set of biochemical and immune assays allows the selection of patients subject to lipostabil treatment and provides additional criteria for the assessment of its efficiency.
71	Metabolic	Huang et al.	2016	Non-alcoholic fatty liver disease of liver stagnation and spleen deficiency pattern treated with acupoint embedding therapy: a randomized controlled trial (article in Chinese)	Open-label comparing acupunture to EPL therapy	n=180	NR	NAFLD	polyene phosphatidylcholine capsules (essentiale)	228 mg/capsule, 2 capsules each time, three times a day for 6 months	For TCM syndrome score, the total score in the embedding therapy group was lower significantly than that in the western medication group (P<0. 05) For liver enzymology and blood lipid, the levels of serum alanine transaminase (ALT), serum glutamic oxalacetic transaminase (AST), total cholesterol (TC) and triacylglycerol (TG) in the embedding therapy group were reduced significantly as compared with those in the western medication group (all P<0. 05 For abdomen B-ultrasound examination, the fatty liver degree in the embedding therapy group was relieved significantly as compared with that in the western medication group (P< 0. 05) For clinical efficacy, the total effective rate was 89. 8%o (79/88) in the embedding therapy group, higher significantly than 76. 7% (69/90) in the western medication group(P<0. 05).
72	Metabolic	Ozerova et al.	2005	Simvastatin and Preparation of Polyunsaturated Phospholipids Produce Similar Changes in the Phospholipid Composition of High-Density Lipoproteins during Hypercholesterolemia	An open-label trial comparing EPL to simvastatin	n= 20	40-65	coronary heart disease & high LDL-C	Lipostabil	2 capsules of 0.3g, 3x/day for 8 weeks	Simvastatin therapy decreased total CH and LDL CH (by 30.3 and 42.5%, respectively), had no effect on triglyceride concentration, and increased HDL CH content (by 6.8%). PUPL had no effect on blood lipid content. We revealed only a slight increase in the concentration of HDL CH (by 4.7%).
73	Metabolic	Kirsten et al.	1994	Polyenylphosphatidylcholine improves the lipoprotein profile in diabetic patients	DB-RCT	n=30	NR	Type II DM with hyperlipidemia	3-sn-polyenylphosphatidylcholine (PPC) or placebo	2.7 g daily, orally over a 2-month period, then one month observation	Serum LDL cholesterol, total cholesterol, HDL cholesterol, and triglycerides were determined on days 1, 14, 28, 56, and 84. After 56 days of treatment with PPC, the primary variable of effectiveness, LDL cholesterol, decreased significantly (p = 0.0174) by 17% from 191 +/- 31 to 159 +/- 36 mg/dl, whereas values did not change in the placebo group. Total cholesterol (TC) in serum decreased by 16% from 303 +/- 22 to 255 +/- 23 mg/dl with PPC. In the placebo group, only a slight decrease from 292 +/- 27 to 289 +/- 41 mg/dl occurred. Mean serum triglyceride (TG) levels fell by 9% from 194 +/- 32 to 177 +/- 27 mg/dl in the PPC group. In the control group, values increased from 193 +/- 34 to 202 +/- 41 mg/dl. The differences in LDL, TC and TG between the treatment groups were statistically significant; p = 0.0014, p = 0.0001 and p = 0.007, respectively. HDL cholesterol in serum increased 12% from 50 +/- 10 to 55 +/- 13 mg/dl after PPC application. The control group did not show any alteration of the mean HDL cholesterol level at any time.
74	Metabolic	Zeman & Stolba	1995	The effect of polyene phosphatidylcholine administration on lipid metabolism and glucose tolerance in patients with hyperlipoproteinemia IIB	DB-RCT	n=30	NR	hyperlipoproteinemia type IIB and hypoalfacholesterolemia	Lipostabil forte R	orally in a daily dose 2.7 g for three months	Administration of PPC to 30 patients with hyperlipoproteinemia type IIB and hypoalfacholesterolemia led to a significant rise of HDL-cholesterol, HDL3-cholesterol, and plasma apolipoprotein A-I concentrations in comparison with the group treated with placebo. At the same time, plasma apolipoprotein B concentration slightly increased. Blood glucose, immunoreactive insulin, and non-esterified fatty acid concentrations during the oral glucose tolerance test didn't change significantly after PPC administration.
75	Metabolic	Kirsten et al.	1989	Reduction of hyperlipidemia with 3-sn-polyenyl-phosphatidylcholine in dialysis patients	DB-RCT	N=20	NR	dialysis & hyperlipidemia	3-sn-polyenyl-phosphatidylcholine (PPC) mornings and evenings	3 x 450 mg (2.7 g daily, 6 capsules) or placebo Six weeks treatment was followed by a two-week wash-out phase.	PPC caused a significant decrease in total cholesterol (-37.8 mg/dl) two weeks after treatment begin (2 p less than 0.001). This decrease remained constant during the duration of treatment. Two weeks after PPC application a decrease in LDL-cholesterol had occurred (-32.0 mg/dl) (2 p less than 0.01) as compared to stable placebo values. Significant PPC induced decreases in triglycerides occurred four (-58.2 mg/dl; 2 p less than 0.001) and six weeks (-43.3 mg/dl; 2 p less than 0.01) after initiation of treatment, as compared to the placebo group (four weeks: +5.7 mg/dl and six weeks: -11.4 mg/dl). Side effects in the PPC group were equivalent to those reported in the placebo group. This study shows that PPC is an effective antihyperlipidemic agent in dialysis patients.
76	Metabolic	Noseda et al.	1985	Modification of serum lipids, lipoproteins and apoproteins AI and B in patients with hyperlipidemia Type IIa and IIb using polyenylphosphatidylcholine (article in German)	DB-RCT	n=27	NR	type II hyperlipidemia	14 sn-polyenylphosphatidylcholin (PPC)	three times 450 mg b.i.d	In all patients, and also in the two subclasses of patients with type IIa and type IIb hyperlipidemia, total cholesterol and LDL cholesterol were lowered significantly by PPC. The other parameters showed only minor variation. There was a downward trend in apoprotein B, triglycerides and VLDL cholesterol, and an upward trend in apoprotein AI, with virtually unchanged HDL cholesterol. None of these variations was significant compared with placebo. The fall in LDL cholesterol with unchanged HDL cholesterol caused a statistically significant decrease in the LDL cholesterol/HDL cholesterol ratio, thus supporting the hypothesis of an antiatherogenic property of PPC, as demonstrated experimentally in various animals.
77	Metabolic	Kukes et al.	1978	Use of the preparation Essenciale in chronic ischemic heart disease (article in Russian)	Observational	n=34	NR	ischemic heart disease	Essentiale	NR	The efficacy of the drug "essentiale" is discussed on the basis of observation over 34 patients suffering from ischemic heart disease with functional hepatic insufficiency and types IIa and IIb hyperlipoproteinemia. Its normalizing effect on the indices of lipid metabolism the flow of blood in the leg and foot, the vascular tone, and liver function is shown.
78	Metabolic	Pristautz	1975	The therapeutic value of "Essential" phospholipids	RCT	n=73	NR	hyperlipidemia	Lipostabil, Lipostabil forte, & placebo	one month,	The effect on the serum lipid level, lipoprotein electrophoresis, coagulation, coronary and peripheral vascular diseases, blood pressure and glucose tolerance was examined. Lipostabil caused a significant decrease of the serum triglyceride level in Type IV. To us, the use of "Essential" phospholipids alone does not appear to be sufficient for the drug therapy of hyperlipemia, but it might play a supporting role in the treatment.
79	Metabolic	Kuska & Kokot	1975	Insulin Secretion in Patients With Chronic Hepatitis Treated With Lipostabil (paper unavailable online)	Open-label trial	n=12	NR	chronic hepatitis	Lipostabil	2 weeks	In 12 patients with chronic hepatitis the carbohydrate tolerance and insulin secretion after intravenous and oral glucose loading were determined before and after lipostabil treatment. A significant rise of fasting insulinemia and hypersecretion of insulin after intravenous glucose loading were observed. After oral glucose loading the rise of insulinemia was significantly lower in patients than in healthy controls, despite a greater increase in glycemia. Administration of lipostabil for 2 weeks failed to exert any significant effect on carbohydrate intolerance and disturbances in insulin secretion, which were present in patients with chronic hepatitis.
80	Metabolism	Olthof et al.	2005	Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men	DB-RCT crossover	n=26	NR	Healthy men with mildly elevated homocysteine	PhosChol	one-half the daily supplement dose 2 times/d for two weeks, then washout period 2 weeks and then other group 34 g	The daily dose of phosphatidylcholine supplement was well tolerated by the subjects, but dyspepsia was reported more frequently with phosphatidylcholine treatment than with placebo treatment Fasting plasma tHcy was 18% lower after subjects had ingested phosphatidylcholine for 2 wk than after placebo treatment On the first day of phosphatidylcholine supplementation (ie, after a single dose), the increase in plasma tHcy 6 h after methionine loading was 15% lower than that on the first day of placebo treatment (Table 3). On the last day of phosphatidylcholine supplementation, the increase in plasma tHcy 6 h after methionine loading was 29% lower than that after placebo treatment Serum folate concentrations were significantly lower after phosphatidylcholine (x SD: 10.9 3.4 nmol/L) than after placebo (11.8 3.1 nmol/L) treatment (P 0.04). Concentrations of vitamin B-6 were significantly higher after phosphatidylcholine (5323 nmol/L)than after placebo (4917 nmol/L) treatment (P 0.05). Vitamin B-12 concentrations did not differ significantly between the 2 treatment periods. Serum alkaline phosphatase concentrations were significantly lower after phosphatidylcholine (64 13 U/L) than after placebo (68 14 U/L) treatment (P 0.001). Concentrations of alanine aminotransferase, aspartate aminotransferase, -glutamyltransferase, and creatinine did not differ significantly between treatments Serum triacylglycerol concentrations were significantly higher after subjects ingested phosphatidylcholine for 2 wk (2.00 1.27 mmol/L) than after they ingested placebo (1.77 1.15 mmol/L) (statistical analyses performed on logtransformed values, P 0.001). Serum concentrations of total, LDL, and HDL cholesterol did not differ significantly between treatment periods.
81	Metabolism	Mel'chinskaia	2000	Hypolipidemic Effects of Alisat and Lipostabil in Patients with Diabetes Mellitus (article in Russian)	Open-label trial	n=121	36-66	DM Type II	Lipostabil	900 mg/day for 52 weeks	lipostabil (900 mg/day) in baseline levels of total cholesterol (TC) above 6.5 mmol/l lipostal treatments reduced TC levels from 7.07 +/- 0.24 to 5.92 +/- 0.30, LDLP cholesterol from 5.54 +/- 0.25 to 4.04 +/- 0.34 mmol/l Lipostabil changed LDLP cholesterol and triglycerides from 0.51 +/- 0.05 to 0.33 +/- 0.03 mmol/l and from 2.54 +/- 0.25 to 1.66 +/- 0.15 mmol/l, respectively, while HDLP cholesterol rose from 1.22 +/- 0.10 to 1.55 +/- 0.07 mmol/l. Alisat did not change significantly.
82	Metabolism	Blaton et al.	1972	The Effect of Essential Phospholipids on Plasma Lipid and Fatty Acids in Hyperlipidemia	Open-label	57	35-91	Hyperlipidemia, Hypertriglyceridemia	EPL	20 ml (5 %) i.v. during 14 days	significant changes were seen in the subgroup of hyperlipidemic patients but not hypertriglyceridemia patients total lipids and cholesterol lowered significantly
83	Metabolism	Cantafora et al.	1992	Effect of intravenous polyunsaturated phosphatidylcholine infusion on insulin receptor processing and lipid composition of erythrocytes in patients with liver cirrhosis	Open-label	13	27 to 70	liver cirrhosis	PPC	i.v. 2 g day-’ for 3 days	the average dose of 33.3 k 2.0 mg Kg-' b.w. day-', caused a significant increase in the total amount of erythrocyte PL. This increase persisted until the 3rd day after the end of treatment (6th day of the experimental time). By the end of experimental time (14th day) the PL levels decreased until there was no significant difference with basal values The processing of insulin receptors, measured by determining the amount of insulin-induced receptor internalization, or down- regulation (DR), was favourably affected by the treatment. The erythrocytes of the patients, which generally did not show insulin receptor down-regulation capabilities before starting the treatment (i.e., subjects with negative values of DR), showed a progressive improvement in receptor processing ability up to the 3rd day after the end of treatment. Down regulation subsequently decreased without reaching the basal value by the end of the study.
84	Metabolism	Ellithorpe et al.	2015	Blood homocysteine and fasting insulin levels are reduced and erythrocyte sedimentation rates are increased with a glycophospholipid-vitamin formulation: a retrospective study in older subjects	Retrospective	35	60.7	CFS	Advanced Physician’s FormulaTM with NTFactor®	NR	A retrospective study was initiated to determine if Hcys levels and other blood markers were altered in subjects taking an oral functional food supplement containing a mixture of phosphoglycolipids (NT Factor®) and vitamins. Methods: Thirty-five patients (28 females, 7 males, Av. Age=60.7±9.6 years) who had used the functional food Advanced Physician’s FormulaTM with NTFactor® in tablet form each day were enrolled in a retrospective study on blood chemistry. This retrospective study followed a prospective study on the use of the same supplement to reduce fatigue in patients with chronic fatigue. Participants were patients with chronic fatigue syndrome (myalgic encephalomyelitis) or other fatiguing illnesses. Subjects had blood drawn over a 6-month period, and routine blood testing was performed. In this laboratory study the results were analyzed for differences, and statistical analyses were performed. Results: All participants responded in the study and showed an average reduction of 31.8% in Hcys levels (from 10.85±0.42 to 7.40±0.42 µmol/L; t-test, p
85	Musculoskeletal	Islamova & Grinio	1989	Effect of Essentiale on the blood lipid indicators in progressive Duchenne muscular dystrophy (article in Russian)	Open-label	NR		Duchenne Muscular Dystrophy	Essentiale	NR	The authors showed a positive effect of the drug essential on both the lipid metabolism and motor function of their patients. The effect was most pronounced at initial stages of the disease.
86	Pharmacokinetics	Gundermann et al.	2011	Activity of essential phospholipids (EPL) from soybean in liver diseases	Review 248 clinical studies, out of these 46 single-blind and 21 double-blind trials have been conducted with EPL for liver disease. 18 studies in children			main indications were fatty infiltration, chronic hepatitis, toxic liver damage, fibrosis/cirrhosis and acute viral hepatitis		doses varied from 525-6000 mg/day orally 250-3000 mg/day i.v. duration varied from a few weeks up to 5 years	Phosphatidylcholines are indispensable for cellular differentiation, proliferation, and regeneration, as well as for the transport of molecules through membranes. They control membrane-dependent metabolic processes between the intracellular and intercellular space, maintain and promote the activity and activation of membrane-bound proteins such as enzymes (e.g., Na -K -ATPase, lipoprotein lipase, lecithincholesterol acyltransferase (LCAT) and cytochrome oxidase) and receptors (e.g., of insulin), and contain bound polyunsaturated fatty acids to be released on demand as precursors of cytoprotective prostaglandins and other eicosanoids. They are a source of second messengers in cell signaling (e.g., of diacylglycerol), contain phosphate for cellular processes including ATP formation, participate in fat emulsification in the gastrointestinal tract and bile, are a determinant of erythrocyte and platelet aggregation, and influence immunological processes at the cellular level. For the cellular biosynthesis of phosphatidylcholine molecules, 5,600 cal/Mol or 8 moles of ATP are needed The absorption rate following oral administration of the labeled EPL within 24 h was higher than 90% in animals and humans [80, 157]. In man, the maximum concentration in blood six hours after oral administration of the labeled substance was about 20% of the administered dose and, thus, approximately four times that measured in rats and monkeys [157]. In blood, phospholipid fractions of the lipoproteins exchange with EPL, with EPL being taken up preferentially by HDL particles [156–158]. EPL is primarily incorporated into the liver, with minor incorporation into other organs such as the gastrointestinal tract, spleen, lung, muscles, kidneys and brain [48, 80, 157]. Analytic examinations of the incorporated H/C-EPL showed that radioactivity was primarily localized in the membrane-containing fractions, with the distribution being ubiquitous in all liver cell fractions [48, 80, 156–158]. Renal excretion after a single dose in the first eight days was 17.4% of the administered dose in rats and 17.7% in rhesus monkeys; 15% was expired by breathing [48]. As the excretion in the feces was low, with 3–8% of the dose excreted in the first 5–7 days in rats [80], a considerable part of the EPL must have accumulated within hepatocytes and other cells, blood corpuscles and lipoproteins Regardless of the origin, damage to liver cell membranes and the organelles is generally present in liver diseases that are associated with reduced phospholipid levels, altered phospholipid composition and/or decreased membrane fluidity. Liver function is inhibited by reduced membrane fluidity that leads to impaired membrane-associated enzyme, receptor and carrier activities. Under chronic conditions, these can lead to altered collagen metabolism, promoting the formation of fibrosis and cirrhosis. Because EPL corresponds to membrane-located phospholipids in its chemical configuration, toxic reactions are not expected, and side effects are rare and weak. In all clinical studies, EPL was well tolerated. Serious adverse drug reactions were not observed either in the inpatients or during long-term treatment of the outpatients. The intravenous form of EPL contains deoxycholate as a solvent and was not used for longer than 2–4 weeks in the trials. No drug interactions with EPL are known
87	Pharmacokinetics	Cohn et al.	2010	Dietary Phospholipids and Intestinal Cholesterol Absorption	Review						measurement of cholesterol absorption, which was estimated by measuring the difference in luminal cholesterol concentration at distances 10 cm and 50 cm downstream of the infusion site. The relatively large amount of PL that was infused luminally (150 mg/kg/hr) not only blocked absorption but actually “extracted” cholesterol from the intestinal mucosa, resulting in ‘negative’ absorption values of −45 ± 2% compared to 40 ± 4% obtained in control subjects. A less invasive and more physiological assessment was carried out by the same laboratory several years later. In this study, 10 hypertriglyceridemic patients (nine men and one woman) were treated for five weeks with orally administered safflower oil (7 grams/day), followed by five weeks of treatment with lecithin (10 grams/day). The amount and type of fatty acids in the two oral supplements (given as a single dose each morning) were similar. Cholesterol adsorption was measured during the 2nd or 3rd week of each treatment in seven patients. Although lecithin treatment had no discernible effect on plasma lipid levels, it significantly increased the molar percent of bile acids and decreased the molar percent of lecithin in gall bladder bile. It also had a small but significant inhibitory effect on cholesterol absorption (42 ± 2% v 36 ± 2%, P < 0.05) A third study investigated the effect of orally administered lecithin on plasma and whole body lipid metabolism in two normolipidemic subjects and six patients with familial hypercholesterolemia [31]. A fat-modified diet was given for 10 days before 10 grams of polyunsaturated fatty acids (PUFA) were replaced for a further period of 10 days by 18 grams of polyunsaturated PC. The two dietary regimes contained similar calories, and similar amounts of cholesterol and polyunsaturated fatty acids. No Nutrients 2010, 2 123 significant change was observed in total plasma triglyceride, cholesterol or PL levels when PC was added to the diet. Similarly, no significant change occurred in LDL or HDL cholesterol concentrations. In contrast, fecal sterol analysis in six individuals revealed a consistent increase in fecal neutral sterol excretion (69%) and a negative sterol balance (−1,362 ± 232 vs. −793 ± 222 mg/day) during the PC vs. PUFA supplementation periods. No evidence was found for a change in the concentration of bile acids, PL or cholesterol in bile. Thus, although cholesterol absorption was not measured directly, indirect evidence was obtained for reduced intestinal cholesterol uptake during PC supplementation
88	Pharmacokinetics	Nicolson & Ash	2017	Membrane Lipid Replacement for chronic illnesses, aging and cancerusing oral glycerolphospholipid formulations withfructooligosaccharides to restore phospholipid function in cellularmembranes, organelles, cells and tissue	Review	N/A	N/A	N/A	N/A	N/A	There are multiple mechanisms for absorption of orally ingested glycerolphospholipids. The ingested phospholipids can be degraded into their constituent parts and these components absorbed; they can be taken in as intact molecules without degradation, or they can be absorbed as small lipid micelles, liposomes or phospholipid globules. When present in excess in the gastrointestinal system, most phospholipids are absorbed undegraded. The process appears to be driven by mass action or a ‘bulk flow’ process. When in large excess, intact MLR phospholipids have an advantage in being able to reach their final destinations without significant degradation The chain length and saturation of the attached FAs of the phospholipids determine membrane packing and fluidity. Unsaturated FAs, such as oleic acid and linoleic acid, confer a high degree of conformational flexibility of the unsaturated hydrocarbon chains within membranes due to their occupying a slightly wedge-shaped space, which results in looser packing and a more fluid membrane. In contrast, saturated FA, such as stearic acid and palmitic acid, confer membrane rigidity, and this results in a less fluid or more rigid, more organized membrane. MLR glycerolphospholipids taken orally are usually absorbed in the upper small intestines as individual molecules or their constituent parts, or when present in excess, they can be transported relatively intact in small phospholipid micelles, globules or liposomes. Some hydrolysis of glycerolphospholipids occurs in the stomach, but most phospholipid enzymatic degradation takes place in the small intestine. There FA and other parts of degraded glycerolphospholipids are transported across the epithelial cell barrier. However, when present in the gastrointestinal system at high concentrations, most glycerolphospholipids are absorbed relatively undegraded in phospholipid micells, globles and small liposomes in an endocytotic process, not as individual molecules or their constitute parts. This could be an evolutionary adaptation to enhance phospholipid transport and thus survival when high concentrations of essential foods are only intermittently available. Glycerolphospholipid absorption in the upper intestines has been found to be very efficient. After a large meal, over 90% of glycerolphospholipids are absorbed and transported into the blood within six hours In the blood circulation limited amounts of glycerolphospholipids are usually found in carrier molecules, such as lipoproteins, or in the cell membranes of erythrocytes. However, when present in excess, they can also be found in blood in lipid globules, liposomes and other forms One problem with direct incorporation of dietary MLR polyunsaturated phospholipids into membrane structures is that they can be oxidized and degraded during their storage, ingestion, digestion and adsorption in the intestinal lumen. This has been accomplished by complexing MLR phospholipids with specific fructooligosaccharides, called inulins, which insert between the head groups of glycerolphospholipids and protect them from excess temperatures, acidity, phospholipases and bile salts. Inulins also protect MLR glycerolphospholipid FA from oxidation Once phospholipids like PC are enriched in the plasma membranes of the cells of the colonic mucosa, they appear to help protect this structure from pathogenic processes like ulcerative colitis and other chronic inflammatory conditions. It has been proposed that they do this by modulating the signaling state of the mucosa, a regulatory component of the inflammatory signaling pathway In man, the amounts of membrane phospholipids exchanged and preferentially transported by HDL lipoproteins are more than 20-times the amounts transported by erythrocytes For example, the average uptake of total dietary membrane lipids is considered to be in the range of 2–6 g per day Plant sources of polyunsaturated membrane glycerolphospholipids, such as legumes or cabbage, are thought to be a good source for dietary MLR supplementation . However, the amounts of plant material, such as soy beans, required to obtain a daily dose of approximately 1.8 g of membrane phospholipids is approximately 15 kg of beans. Oral supplements for MLR utilize mixtures of glycerolphospholipids and unsaturated FA, such as n-3 and n-6 unsaturated FA, and other lipid components derived from various sources: legumes, milk, liver, fish, krill, among other sources NTFactor®, which also contains probiotic bacteria, growth media and other ingredients, and NTFactor Lipids®, without these additives, come in several oral forms, but almost all contain from 1–2 g of phospholipids per dose The recommended optimal daily oral dose of NTFactor Lipids® for most clinical conditions has been estimated at 2–4 g per day, and more recently at least 4 g per day, whereas its anti-aging use has been proposed at 2 g per day Although taking a single class of glycerolphospholipid alone, such as PS, has been shown to have health benefits, the use of more complex mixtures of membrane phospholipids containing PC, PS, PE, PI, etc. are considered more beneficial Administration of membrane phospholipids (“essential” phospholipids or EPL) can deliver high phospholipid concentrations without the need for fructooligosaccharides to inhibit intestinal disruption, but they are still susceptible to enzymatic and oxidative damage. In addition, daily intravenous delivery comes with some risk for adverse events, such as infection, blood vessel damage, thrombosis, pruritus, dyspnoea and urticaria Most clinical studies have used oral MLR phospholipids in the dose range of 1.5–4 g per day or intravenous administration in the dose range of 0.5–2 g per day. MLR phospholipids have been obtained from soy, egg, milk and marine sources and have been used in doses over 4 g per day orally or intravenously in doses over 2 g per day with no adverse effects. In a few cases does up to 45 g of MLR glycerolphospholipids were given orally without any adverse effects. In fact, the use of MLR phospholipids actually reduced the adverse or side effects of drugs and other treatments
89	Pharmacokinetics x	Oette et al.	1995	Absorption of di-linoleoylphosphatidylcholine after oral administration (article in German)	Pharmacokinetics	n=11	NR	healthy	d15-DLPC	single oral dose	A single oral dose of d15-DLPC loaded with deuterium 9 times in the choline and 6 times in the linoleic acid of the 1-position was given to volunteers. Sera from 11 blood samples taken within 48 h after application were examined by means of mass spectrometry with regard to d9-choline and d6-linoleic acid in the 1- and 2-position of serum phosphatidylcholines (PC) as well as in the serum triglycerides. d9-choline, i.e. the total of d15-PC and d9-PC, showed maximum values of 5.6% of the total serum PC concentration. Normally, about 1.3% of PC in the human serum is DLPC. Serum 1-linoleoyl-PC was increased by 32-40% after oral application of d15-DLPC. A minor uptake of d6-linoleic acid into the 2-position of serum PC, which is rich in linoleic acid, and into the serum triglycerides was observed with peak values of 2.3% and 6.1%, resp. The uptake of polyunsaturated PC species like DLPC and 1-linoleoyl-PC into the liver after oral application of drugs containing such species in high amounts like "essential" phospholipids with about 50% of DLPC let expect therapeutic effects on membranes into which this special species is incorporated.
90	Psoratic arthritis	Ipatova et al.	2003	Hemorheological and clinical efficiency of a new phospholipid hepatoprotective drug Phosphogliv in patients with psoriatic arthritis (article in Russian)	Case series	NR	NR	psoriatic arthritis	Phosphogliv	0.6 g/day for 3 months	In the present study, it was used for the treatment of patients with psoriatic arthritis, accompanied by severe damages to blood rheology A considerable decrease of erythrocytes aggregability was observed after the treatment. There were no changes in total blood viscosity. The clinical state of patients markedly improved after the treatment. A simultaneous decrease of blood C-reactive protein level suggests the weakening of inflammation. The mechanism of these effects may involve the direct influence of the phospholipid on erythrocyte membranes and/or with indirect influence through the improvement of liver function. The results show that Phosphogliv inclusion in therapy improved the state of patients with psoriatic arthritis.
91	Renal	Neimark et al.	1998	Use of Isradipine and Lipostabil for Protection of the Kidney During Extracorporeal Lithotripsy (article in Russian)	Open-label	NR	NR	nephrolithiasis	Lipostabil	12 weeks before lithotripsy and 4 weeks after	Isradipine proved a good corrector of renal function after lithotripsy as it decreased enzymuria, promoted normalization of the activity of alkaline phosphatase, gamma-glutamyl transferase, alpha-glucosidase and lactate dehydrogenase to the end of the first postoperative month. This indicates quicker recovery of renal parenchyma after ESWL. Lipostabil also improved enzymic indices. Its moderate protective action on renal parenchyma normalized levels of some enzymes one month after ESWL.
92	Renal	Chan et al.	1991	Effect of Phosphatidylcholine on Ultrafiltration in Patients on Continuous Ambulatory Peritoneal Dialysis	RCT	n= 8	51	renal failure, dialysis for 24 months	Essentiale forte	300 mg 3 times daily, orally	no significant difference in ultrafiltration at the end of the treatment period no difference between the treatment and placebo groups at the end of two months in solute and glucose transfer serum TC, TG, HDL-C and apoB remained unchanged in both groups apoA was significantly increased from 1.22 to 1.51 in the Essentiale group and from 1.11 to 1.41 in the placebo group. No inter-group differences were observed no change in serum Hb, reticulocyte count, SGPT, and mena systolic and diastolic blood pressure no significant change in overnight peritoneal fluid phospholipid content after 2 months of treatment. none of the patients complained of any side effects
93	Reproductive	Maniyozova & Negmatshaeva	2016	Use of essentiale Forte in complex treatment of Antiphospholipid syndrome in women	Open-label	n=43		Pregnant women with AP syndrome	Essentiale forte N	conventional therapy + 1 tablet 10 t.i.d. within 1 month prior to estimated pregnancy with further maintaining dose depending on hemostasis indices over a period of pregnancy and enzymatic preparation Serrata.	promotes bringing the pregnancy to term significant changes to hematostatic markers
94	Reproductive	Anderson et al.	2011	Lecithin Supplements and Breast Cancer Risk	Observational	3101 + 3471	25-74	Breast cancer	Lecithin	NR	Ever-use of lecithin supplements was associated with reduced breast cancer risk (age-adjusted OR = 0.77 [95% CI = 0.62–0.97]) Although the association appeared stronger in postmenopausal women (age-adjusted OR = 0.71 [0.55–0.92]) than premenopausal women (0.96 [0.62–1.49]) (Table), the multiplicative interaction between lecithin supplement use and menopausal status was not statistically significant (likelihood ratio test P interaction = 0.25
95	Respiratory	Zhang et al.	2019	Polyene phosphatidylcholine protects against radiation induced tissue injury without affecting radiotherapeutic efficacy in lung cancer	Retrospective analysis	133	NR	NSCLC	PPC	3 × 456 mg per day over the radiotherapy period 5-6 weeks	a retrospective analysis was caried out in 133 NSCLC patients to assess impact of daily PPC administration on radiation pneumonitis. Uni- and multivariate analyses suggested that daily PPC intake is significantly associated with reduced risk in developing symptomatic radiation pneumonitis in NSCLC patients. In comparison to patients without PPC supplementation, patients who received PPC benefited from a slower decline in lung function post radiotherapy. Total body irradiation in mice further confirmed that PPC administration protected against radiation induced fatal tissue damage and this protective effect was directly linked to increased cellular antioxidant defense. Radiation resulted in significant growth inhibition of cultured LLC and A549 cells as well as of LLC xenografted tumors, how-ever, this was not affected by PPC treatment. In conclusion, PPC protects against radiation induced injury of healthy tissues and thus may serve as meaningful adjuvant for radiotherapy in NSCLC as well for other cancer entities to dampen adverse effects.
96	Risk	Tang et al.	2013	Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk	Observational	4007	NR	NR	Dietary PC	NR	We quantified plasma and urinary levels of TMAO and plasma choline and betaine levels by means of liquid chromatography and online tandem mass spectrometry after a phosphatidylcholine challenge (ingestion of two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine) in healthy participants before and after the suppression of intestinal microbiota with oral broad-spectrum antibiotics. We further examined the relationship between fasting plasma levels of TMAO and incident major adverse cardiovascular events (death, myocardial infarction, or stroke) during 3 years of follow-up in 4007 patients undergoing elective coronary angiography. Time-dependent increases in levels of both TMAO and its d9 isotopologue, as well as other choline metabolites, were detected after the phosphatidylcholine challenge. Plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after withdrawal of antibiotics. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (hazard ratio for highest vs. lowest TMAO quartile, 2.54; 95% confidence interval, 1.96 to 3.28; P<0.001). An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P<0.001), as well as in lower-risk subgroups.
97	Risk	Meter & Shea	2017	Dietary Choline and Betaine and Risk of CVD: A Systematic Review and Meta-Analysis of Prospective Studies	Systematic review	6 studies	NR	NR	Dietary choline	NR	no association between incident CVD and choline or betaine in the diet discrepancies in CVD mortality and choline consumption studies need to be investigated study was funded by a grant from the "Egg Nutrition Center"
98	Risk	Cho et al.	2020	Effect of Choline Forms and Gut Microbiota Composition on Trimethylamine-N-Oxide Response in Healthy Men	DB-RCT crossover	37	NR	Healthy	choline either as choline bitartrate or phosphatidylcholine, or no choline control	600 mg	Compared to phosphatidylcholine and no choline control, choline bitartrate yielded three-times higher plasma TMAO AUC (p=0.01; Figure 3) and 4.4-times higher plasma TMAO maximum increase from baseline (p<0.0001) Gut microbiota composition differed (permutational multivariate analysis of variance, PERMANOVA; p=0.01) between high-TMAO producers (with ≥40% increase in urinary TMAO response to choline bitartrate) and low-TMAO producers (with <40% increase in TMAO response). High-TMAO producers had more abundant lineages of Clostridiumfrom Ruminococcaceae and Lachnospiraceae compared to low-TMAO producers
99	Risk	Ivashkin & Kashukh	2019	Impact of L-carnitine and phosphatidylcholine containing products on the proatherogenic metabolite TMAO production and gut microbiome changes in patients with coronary artery disease	Case-control	59	>50	CAD	PC products	NR	In the first part, a comparison was made between the diet of patients with CAD (n=29) and healthy volunteers (n=30) over the age of 50 with respect to the frequency of intake of L-carnitine and phosphatidylcholine containing products. All participants underwent blood sampling and stool tests to assess the concentration of TMAO and the composition of fecal microflora. The second part of the study was dedicated to assessing the correlation between TMAO blood concentration in patients with CAD (n=89) and the frequency of intake of L-carnitine and phosphatidylcholine containing products. Patients with CAD comparing to healthy people among the predecessor products of TMAO consumed red meat, dairy products more often, eggs and fish less often. TMAO concentration in patients with CAD was higher than in healthy volunteers (1036.4±748.2 vs 376.5±147.9 ng/ml, p=0.0001). Analysis of fecal microflora in patients with CAD revealed an increase number of bacteria from Verrucomicrobiaceae family (p<0.05) and Enterobacteriaceae family (p<0.05), of the Escherichia/Shigella genera (p<0.05), there was a trend to increased number of Ruminococcus (р=0.065), Clostridium XlV (b) genera (р=0.10). Correlation between TMAO concentration and frequency of red meat, eggs, and dairy products consumption was estimated in patients with CAD (r>0.525, р<0.05). Patients with CAD consume more precursors of TMAO, have higher blood TMAO concentrations compared to healthy volunteers. Fecal microflora of patients with CAD contains a greater number of gut bacteria related to trimethylamine producers compared to healthy volunteers. Reducing the number of L-carnitine and phosphatidylcholine containing products in the diet of patients with CAD may affect the decrease in the proatherogenic metabolite TMAO concentration.
100	Risks	Van Parys et al.	2019	Dietary choline is related to increased risk of acute myocardial infarction in patients with stable angina pectoris	Retrospective analysis	1981	62	CAD	dietary PC	NR	PC is hydrolyzed by phospholipase A2 to lysoPC prior to absorption in the enterocyte LysoPC can be either reacetylated to PC or further broken down to glycerophosphocholine, and finally free choline PC enters the bloodstream through the lymphatic system incorporated in chylomicrons, thereby being delivered directly to peripheral tissue (muscle and adipose) before reaching the liver The majority of choline in both diet and body is in the form of PC. Absorbed free choline is mainly used for PC formation via the Kennedy pathway, which is in its turn secreted into bile and very-low-density lipoproteins (VLDL). The amount of PC in the bile largely exceeds the dietary supply (respectively 11 g/day vs 1-5 g/day). Approximately 95% of biliary PC is reabsorbed and 40% is returned to the liver, implying an extensive enterohepatic choline cycle. Endogenous PC formation occurs via the phosphatidylethanolamine N-methyltransferase 45 pathway, where PC is formed from phosphatidylethanolamine (animal studies) Higher plasma choline has been associated with an increased risk of cardiovascular disease (CVD). Choline’s oxidation product, betaine, links choline to the one-carbon metabolism via its role in the betaine-homocysteine methyltransferase reaction where a methyl group from betaine is transferred to homocysteine, forming methionine and dimethylglycine (DMG). Elevated plasma total homocysteine (tHcy) has been linked to increased risk of coronary artery disease (CAD) and plasma DMG levels have been associated with the risk of future acute myocardial infarction (AMI) in the current population. Additionally, previous studies have reported either no or only marginal correlations between plasma choline levels and dietary choline intake. observed increased risk for AMI per 50 mg/d increment of total choline (HR 1.11, 95% CI [1.03, 1.20]) and PC (1.24 [1.08, 1.42]) intakes higher dietary choline intake, more specifically total choline, PC, and SM, was associated with increased AMI risk during long-term follow-up, and the associations appeared to be linear across the intake ranges. The intakes of free choline, phosphocholine, and glycerophosphocholine did not seem to be associated with AMI risk. PC and SM from eggs is associated with beneficial changes in biomarkers related to reverse cholesterol transport and high-density lipoprotein characteristics may exert negative effects through the conversion to trimethylamine by the intestinal microbiota, which is absorbed and transformed in the liver to TMAO by flavin-containing monooxygenase 3 (FMO3) Plasma TMAO might advance atherosclerosis by reduction of reverse cholesterol transport, increased macrophage cholesterol accumulation, upregulation of macrophage scavenger receptors, and augmented foam cell formation, resulting in increased inflammation and low-density lipoprotein cholesterol oxidation Dietary choline intake was inversely associated with plasma tHcy concentrations in our cohort, being in line with several intervention studies showing that choline supplementation lowers plasma tHcy concentrations lowering of tHcy concentrations was not associated with reduced incidence of cardiovascular events in a meta-analysis of 8 randomized trials including 37 485 participants
101	Risks	Zheng et al.	2016	Dietary phosphatidylcholine and risk of all-cause and cardiovascular-specific mortality among US women and men	Retrospective analysis	80,978 women and 39,434 men.	NR	NR	dietary PC	NR	dietary phosphatidylcholine intake was associated with a higher risk of all-cause mortality in both the NHS and the HPFS each 100 mg/d higher phosphatidylcholine intake was associated with an 8% (95% CI: 5%,11%) increment in all-cause mortality analyses to further adjust for the 3 major food sources of phosphatidylcholine (red meat, eggs, andfish) in the model and found that participants in the top quintile of phosphatidylcholine intake still had a 7% (95% CI: 2%, 13%) higher risk of all-cause mortality than those in the bottom quintile in the combined analysis, and the linear trend across quintiles wasretained We also excluded participants who took lecithin (phosphatidylcholine) supplements, and the results did not materially change diabetic participants in the top quintile of phosphatidylcholineintake had a 24% increased risk of all-cause mortality and a 67% increased CVD-mortality risk, whereas the nondiabetic participants in the top quintile had a 9% increased all-cause mortality risk and a 19% increased CVD-specific mortality risk than thosein the bottom quintile in each population circulating TMAO might advance atherosclerosis by disturbing the clearance ofcholesterol in the liver Our previous results showed that participants in the top quintile of dietary phosphatidylcholine intakes had a 34% higher risk of type 2 diabetes than those in the bottom quintile intakes
102	Risks	Richman et al.	2012	Choline intake and risk of lethal prostate cancer: incidence and survival	47,896 men	NR	NR	NR	dietary choline	NR	Choline is highly concentrated in prostate cancer cells, and blood concentrations of choline have been associated with an increased risk of prostate cancer Nearly 50% of choline was consumed in the form of phosphatidylcholine, followed by free choline (24%), glycerophosphocholine (17%), sphingo-myelin (5%), and phosphocholine (4%). men in the highest quintile of choline intake had a 70% increased risk of lethal prostate cancer compared with men in the lowest quintile relation was not appreciably changed after adjustment for important food contributors to choline intake (eg, whole eggs, skim milk, beef or lamb as a main dish, and chicken or turkey without skin) Choline is converted to phosphatidylcholine—a phospholipid necessary for cellmembranes—and choline kinase, the enzyme that catalyzes the first and rate-limiting step in this conversion, is overexpressed inmany human cancers, including prostate cancer
103	Risks	Wilcox et al.	2021	Dietary Choline Supplements, but Not Eggs, Raise Fasting TMAO Levels in Participants with Normal Renal Function: A Randomized Clinical Trial	RCT	n= 82	28	healthy	Choline	(i) hardboiled eggs (N=18); (ii) choline bitartrate supplements (N=20); (iii) hardboiled eggs + choline bitartrate supplements (N=16); (iv) egg whites + choline bitartrate supplements (N=18); (v) phosphatidylcholine supplements (N=10)	Participant's plasma TMAO levels increased significantly in all three intervention arms containing choline bitartrate but daily ingestion of four large eggs (P=0.28) or phosphatidylcholine supplements (P=0.27) failed to increase plasma TMAO levels Platelet reactivity also significantly increased in the three intervention arms containing choline bitartrate (all P<0.01), but not with eggs (P=0.10) or phosphatidylcholine supplements (P=0.79) the form and source of dietary choline differentially contributes to systemic TMAO levels and platelet responsiveness.
104	Sexual	Kiriakova et al.	1998	Therapeutic effect of essential phospholipids on functional sexual disorders in males	Open-label	n=23	23-64	erectile, ejaculatory, libido dysfunction	EPL	Two capsules of EPL (300 mg) were administered orally three times a day for 60 days.	The results indicate a decrease in the number of the patients with erectile dysfunction (P < 0.01) and loss of libido (P < 0.001), and an alteration of ejaculation (P > 0.05) following treatment. The treatment with EPL increased the sperm count, but not to a level of statistical significance: the motility of spermatozoa significantly improved (P < 0.05) (Table 2). we suggest the hypothesis that EPLs are incorporated into a sperm, promoting a significant improvement in motility and viability before/after treatment: erection normal 8/18, ejaculation normal 11/18, libido normal 6/19
105	TC, LDL	Mourad et al.	2010	Influence of Soy Lecithin Administration on Hypercholesterolemia	DB-RCT	n=30	NR	hyperlipidemia	soy lecithin	500 mg/day orally two months	Total cholesterol and LDL were evaluated after soy lecithin administration in hypercholesterolemic patients. One soy lecithin capsule (500 mg/RP-Sherer) was administrated daily. One-two months before the treatment beginning, blood samples were collectedfor total lipids and cholesterol fractions analysis. The results showed a reduction of 40.66% and 42.00% in total cholesterol and of 42.05% and 56.15% in LDL cholesterol after treatment for one and two months, respectively. A significant reduction in total cholesterol and LDL-cholesterol concentrations was observed during the first month of treatment, suggesting that the administration of soy lecithin daily may be used as a supplemental treatment in hypercholesterolemia. no effect on TG levels
106	Type, dose, form	Nicolson	2016	Membrane Lipid Replacement: Clinical Studies Using a Natural Medicine Approach to Restoring Membrane Function and Improving Health	Review	NR	NR	NR	NR	NR	composition of NT Factor table! An intravenous-delivered MLR mixture of glycerolphospholipids (“Essential phospholipids”) can deliver high phospholipid concentrations without the need for inhibiting intestinal disruption However, this product is still susceptible to enzymatic and oxidative damage, and daily intravenous delivery comes with some risk for adverse events, such as infection, blood vessel damage, thrombosis, pruritus, dyspnoea, urticaria, among other potential problems.
107	Types, doses, form	Lüchtenborg et al.	2020	Lipid Profiles of Five Essential Phospholipid Preparations for the Treatment of Nonalcoholic Fatty Liver Disease: A Comparative Study	Comparative analysis (highly biased: funded by Essentiale Forte producers	NR	NR	NR	NR	n/a	Preparation B contained the lowest amount of PtdEtn and one of the highest levels of polyunsaturated fatty acids. In addition, PtdCho 36:4 in particular, was present in Preparation B in abundance. Taken together, these findings provide evidence that this PPC, which also contains a high PtdCho:PtdEtn ratio, may have substantial clinical benefit in the treatment of NAFLD The five PPC preparations investigated in this study included: Esentin Forte (Sunwave Pharma SRL, Romania [Preparation A]) (Sunwave Pharma, 2019); Essentiale® Forte 300 mg (Sanofi Romania SRL [Preparation B]), which is available in 20 countries worldwide (Sanofi, 2019); Fortifikat 500 mg (Terapia, Romania [Preparation C]) (Terapia, 2019a); Fortifikat Forte 750 mg (Terapia, Romania [Preparation D]) (Terapia, 2019b); and Hepatoprotect Regenerator 712.5 mg (S.C. Biofarm S.A. Romania [Preparation E]) (BIOFARM, 2018).

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