Plaquex for Liver Disease
Plaquex is also used as a liver therapeutic. Within 38 years 126 clinical studies were done on over 8300 patients.
Liver damage always involves cell membrane damage. The energy quantity of 5600 cal/Mol required for the cellular biosynthesis of phosphatidylcholine cannot be supplied by the damaged liver cell. This is why exogenous PC is important to restore cell membranes and cell morphology and ultimately cell function.Many different animal studies were done showing that PC diminished the damage of liver cells when given early enough. One of the mechanisms by which it protects liver cells is the inhibition of lipid peroxidation. PC prevents suppression of cellular respiration caused by snake venom, it prevents the loss of glucose-6-phosphatase after intoxication with Carbon Tetrachloride and it helps prevent or postpone liver cirrhosis by inhibiting collagen synthesis in fibroblasts. It reduces fatty deposits in fatty liver thereby preventing and treating fatty liver.
The suggested hepataprotective and hepatotherapeutic action of PC could be corroborated in 7 in-vitro and in 55 in-vivo experiments. In the presently available 55 in-vivo investigations, in which 20 different
models in 5 different animal species were used, mostly such toxic substances were employed which are known to play a role in the origin of liver damage: CCI4, ethanol, galactosamine, acetaminophen, tetracycline, organic solvents, carbon disulphide, thioacetamide, indomethacin and others.
Carbon Tetrachloride Toxicity and PC Studies in Animals
Since the hepatotoxic effect of carbon tetrachloride was first described in 1923, this substance has often been applied in experiments and is considered as one of the best examined models. The damages are attributable to the formation of radicals and to lipid peroxidation. A single administration in mice and rats already produces membrane damage, centrolobular necrosis and fatty degeneration.
of the liver.
The findings of the PC effect from controlled studies demonstrate that the damages induced in the animals can be reduced by intravenous, intraperitoneal or oral administration of PCL at doses between 25 and 3,300mg/kg body weight. The assessment was made on the basis of reduced serum values of transaminases (ALT,AST), LDH and AP, the reduction of lipid values and peroxide formation, as well as on the basis of normalized protein synthesis in liver cells. The findings convey the impression as if it was first of all the mitochondrial (and microsomal) membrane which is protected against CCL4 destruction by the protective oral administration of PC.
After chronic CCI4 intoxication for 9 months, rats showed severe cirrhotic alterations of the liver. The animal group which in addition to CCI4 was given i.m., i.p. or oral PC at doses between 100 and 300 mg/kg b.w. during the last 3 months, in contrast, presented markedly less damages: histology and electron micrographs showed in all cases a reduction of hyperplastic connective tissue,
fibrosis, formation of pseudo-acinus and biliary pseudocanaliculi; the content of liver hydroxyproline was reduced and the collagen/DNA ratio was normalized; on the biochemical level, the transaminase activities minished; mortality was markedly lower than in the controls. The simultaneous PC treatment produced a clear reduction of liver lipids and fatty degeneration of liver cells in rats exposed to chronic carbon tetrachloride intoxication and simultaneous feeding of alcohol. 1,2
Similar results were achieved in animals subjected to chronic and acute ethanol toxicity. PC administration significantly reduced ethanol induced fibrogenesis in baboons. They didn't progress beyond the stage of perivenular fibrosis. Withdrawal of PC accelerated the process of fibrosis to finally cirrhosis. 3
PC reduces Acetaminophen Toxicity
Effect in Intoxication Induced by Paracetamol/ Acetaminophen or by Indomethacin: Paracetamol intoxication, known in man, can be reproduced in the mouse. Centrolobular necrosis develops. On the biochemical level, Increase of lipid peroxidation and transaminases activity as well as reduced liver glutathione are reported. The prophylactic i.v. administration of PC entailed a dosa4ependent correction of the affected parameters and prevented mortality.
PC and immunological/viral liver damage in animal studies
Immunological pathomechanisms are of major importance in liver disease in man. To these pathomechanisms belong autoimmunological reactions and Insufficient Immunological reactions. The latter plays an important role in viral infection. An insufficient immunological reaction against the virus-infected cells leads to a chronic process of cellular infection and extinction of the affected cells. It is known that a hepatitis-B virus infection is important in initiating the disease in many cases of active chronic hepatitis and that sensitization to the liver cell membrane antigen is the autoimmune process responsible for the perpetuation of the liver injury4. The influence of PC on the auto-immunological antibody dependent cell mediated cytotoxicity (ADCC) was studied in rabbits. Rabbits were pre-treated with PC for 6 weeks. Hepatocytes were subsequently isolated and either incubated with antibody-containing sera from patients with HBsAg negative, anti HBs-negative and anti-HBc negative chronic active hepatitis or brought into direct contact with the mitogen-stimulated lymphocytes. The following results were obtained:
In contrast to the studies using hepatocytes isolated from control rabbits not given PC, the antibody-containing sera from patients and the lymphocytes from healthy individuals did not lead to increased ADCC in the hepatocytes obtained from PC-treated rabbits5.
In conformity with experiments in animals, clinical trials were carried out to study the possible effects of PC on liver damage caused by alcohol abuse, halogenated hydrocarbons, treatment with anti-tuberculous agents, or malnutrition. Subjective and objective signs of improvement were seen in the clinical picture, demonstrated on comparison of final results with pretreatment findings by an improvement which was more pronounced in the groups receiving the active preparation; in these patients, a return to normal of test variables was also more frequent. PC increased resistance of the hepatocytes to hepatotoxic agents, particularly when administered concomitantly with known noxious agents such as isoniazid. Clinical assessment of efficacy in intoxication and fatty liver resets on more than 70 clinical trials involving over 4.200 patients.
ALCOHOLIC LIVER DAMAGE
The success of treatment of alcoholic liver damage depends essentially on whether the patient is able to curb his alcohol intake or abstain from drinking entirely. Controlled studies6-11 have shown that administration of PC accelerated elimination of fatty deposits from hepatic tissue. Twenty patients with alcoholic fatty liver or alcoholic hepatitis, most of whom had had diagnostic biopsies, were studied on a double-blind basis against a placebo group of the same size12. Eight weeks after treatment with PC was begun, all variables showed highly significant improvement against control. The PC-treated patients registered a return to normal of the pathologically raised serum levels of AST, ALT, GLDH, AP, LAP, LDH and bilirubin. Gamma-GT, cholesterol and triglyceride reached nearly normal levels. None of the placebo patients showed a return to normal of biochemical values.
A controlled study in which PC was tested against placebo in 40 patients corroborated these findings13. In the actively treated group, the erythrocyte sedimentation rate and serum activities of AST, ALT and of gamma-GT were reduced. Though the group receiving the active preparation had higher baseline values than the placebo-group, their final values at the end of the 12-week treatment period were lower; an initial significant decrease in these values became apparent after 4 weeks already.
DIABETIC FATTY LIVER
In a randomized double-blind study involving a total of 30 patients with fatty liver associated with age-related diabetes, a significant decrease in liver size was observed in the PC group, but in none of the patients of the control group, 6 months from the start of the therapy14.
1,313 patients in total were treated with PC, the duration of therapy being related to the severity of the disease. In contrast to patients receiving basic treatment only, the patients treated with PC usually reported earlier improvement of symptoms such as dyspepsia, feeling of preassure, feeling of tension, sensationof fullness in the epigastrium, nausea and epigastric pain.
Improvement of the clinical parameters (hepatomegaly, ascites) and biochemical tests (AST, ALT, total protein, bilirubin, AP) occurred more rapidly and histological assessment indicated earlier regeneration of the liver in patients treated with PC15-17.
Hospitalization was shortened in the PC-treated patients who were able to return to work sooner compared with the controls. Late sequelae such as progression to chronicity were less frequent.
A randomized double-blind study performed by G.Visco18 corroborated earlier findings from open trials. After 30 days of treatment, HBsAg was no longer detectable in the sera of 15 out
of 30 patients in the PC group compared with 7 out of 30 patients in the placebo group.
56 patients with moderately severe acute or protracted viral hepatitis were treated with PC for 12-60 days depending on the severity of their condition15. The investigators assessed the efficacy of the treatment by means of clinical symptoms, laboratory parameters and liver biopsies.A group receiving conventional treatment was used as a control. Histological assessment revealed cleary better results in the patients treated with PC. Dystrophic and necrotic changes in the liver parenchyma were less pronounced, infiltration by lymphocytes in the portal stroma was reduced, cholestasis was less marked and regeneration of hepatocytes more evident. H.Wallnofer and M.Hanusch also found histological evidence of marked regression of infiltrations and less frequent individual and group necroses in the patients treated with PC.
In a controlled trial involving two groups each consisting of 17 patients with chronic hepatitis, M.Yano et al.19 performed liver biopsies before and 6 months after the beginning of treatment with PC (group A) or placebo (group B). Assessment of liver biopsy specimens was on a "blind" basis. A statistically significant improvement or a trend towards improvement with regard to ballooning of liver cells, appearence of liver cell membranes, focal necrosis and mobilisation of Kupffer cells was observed in the actively treated patients as compared with the control.
Marked improvement of the liver function following PC administration was interpreted as a sign of a favourable effect on the course of the disease in terms of an increase in the metabolic and detoxifying capacity of the liver. A.P. Pogromov et al.20 reported improved well-being in their 25 patients with cirrhosis of the liver. After 90 days of oral treatment with PC nearly all biochemical parameters were found to be within the normal range.
M. Kalab and J. Cervinka21 who treated 30 patients with PC for a period of 6 months also observed marked improvement in clinical and biochemical findings. Raised IgA decreased to normal levels.
P. Fassati et al. 22 studied 61 patients with moderatly severe to severe cirrhosis following type B hepatitis. They compared 34 patients given EPL with 27 patients receiving a vitamin preparation. While in the control group there was almost no change against pre-treatment values, the patients given EPL registered an improvement in liver function. In 5 out of 8 patients given EPL, but in only 1 out of 7 patients in the control group, HBsAg was no longer detectable at the end of the 3-month treatment period.
GALL STONE PREVENTION
In a study carried out by G.Salvioli et al.23 the linoleic acid deficiency in biliary phosphatidylcholine seen in patients with gallstones was corrected by administration of EPL. K.R.Holan et al.24 also observed an increase in the concentration of unsaturated fatty acids in biliary phosphatidylcholine following administration of EPL. J.Toouli et al.25 found an increase in the biliary deoxycholic acid concentration in their patients. A trial performed by L.Stiehl et al.26 showed that a combination of EPL and chenodeoxycholic acid was more effective in reducing the lithogenic index of bile than the individual compounds given alone.
Summary of Clinical Findings
- In clinical studies EPL was given to patients with toxic liver damage, particularly fatty liver of varied origin, intoxication, acute viral hepatitis, chronic hepatitis, cirrhosis of the liver, hepatic coma and in conditions associated with changes in the composition of bile.
- Depending on the severity of their condition the patients were treated for periods of up to one year or even longer.
- The hepatoprotective effect of EPL previously demonstrated in models of experimental liver disease, was shown both in patients receiving an otherwise therapeutic regimen known to be hepatotoxic and in those with manifest toxic liver damage. Comparison with controls indicated an earlier return to normal of hepatic enzyme activity following administration of EPL; fatty degeneration of the liver was less pronounced and structural restoration of damaged liver cells occurred more rapidly. In life- threatening intoxication associated with severe liver injury, EPL reduced the mortality rate and accelerated recovery of the patients.
- In patients with acute viral hepatitis EPL was also effective in speeding up recovery. Both the length of stay in hospital and the recovery phase were significantly shorter in the EPL-treated patients than in the controls.
- Patients with chronic hepatitis of varied origin experienced rapid improvement in well-being. Objective signs in support of this finding were changes towards normal laboratory parameters and in particular, substantial improvement in the histological picture with reduction in portal tract infiltration and piecemeal necrosis, reflecting a marked decrease in disease activity. All patients whose disease had even become inactive had received EPL treatment; in other words, in the controls disease activity was not arrested. EPL was also shown to be effective in cases of HBsAg CAH inadequately controlled with standard immunosuppressive therapy.
- In cirrhosis of the liver the success of treatment was determined by the stage of the disease. The effect of EPL in this condition was manifested as a marked improvement of the patient's sense of well-being and a reduction in free phenol and ammonia concentrations, reflecting amelioration of the oxidative processes and the detoxification capacity of the liver.
1 Comporti, M., E. Burdino, E. Ugazio: Changes in fatty acid pattern of liver microsomal phospholipids in rats treated with Carbon Tetrachloride. Ital. J. Biochem. (Engl.Ed) 20 (1971) 156-165
2 Sakai, Y., M. Isozaki, G. Gouda: Biochemical changes and phospholipid metabolism in subcellular particles of CCL4 poisoned rat liver and their relationship to the etiology of fatty liver. World Congr. Gastroenterol. Proc. 3 (1967) 111-113
3 Lieber, C.S., L.M. De Carli, K.M. Mak, C.I. Kim, M.A. Leo: Attenuation of alcohol induced hepatic fibrosis by polyunsaturated lecithin. Hepatology 12 (1990) 1390-1398
4 W.M. Lee, W.D. Reed,. C.G. Mitchell, R.M. Galbraith, A.L. Eddleston,A.J. Zuckerman, R. Williams: Cellular and humoral immunity to hepatitis-B surface antigen in active chronic hepatitis. Br Med J 1975; 1 doi: https://doi.org/10.1136/bmj.1.5960.705 (Published 29 March 1975) Cite this as: Br Med J 1975;1:705
5 Neuberger, J., J.E. Hegarty, A.L.W.F. eddleston, R. Williams: Effect of polyunsaturated phosphatidylcholine on immune mediated hepatocyte damage. GUT 24 (1983) 751-755
6 Caruso L., C. Trischitta, G. Bertino, M.G. Amore, F. Rapisarda, G. Calcara: Polyunsaturated phosphatidylcholine in the treatment of fatty degeneration of the liver. Clin. Ter. 107 (1983) 279-290
7 Hazuka, V., R. Roubal: La fosfatidilcolina polinsatura complesso vitaminico B nella terapia dell' epatopatia alcoolica. Studio controllato versus terapia standard. Clin. Ter. 123 (1987) 369-375
8 Indovina, I., G. Licata, R. Scaglione, G. Parrinello: Effect of i.v. administered polyunsaturated phosphatidylcholine in hepatopathies. Study on morphology and function with 99m Tc parabutyl-IDA. Epat. 27 (1981) 261-278
9 Indovina, I., A. Scaffidi, R. Costa: The effects of polyunsaturated phosphatidylcholine with vitamins of the B group on the metabolism of SeHTCA in patients with chronic liver disease. Min.Med. 78 (1987) 369-372
10 Sorrentino, F., G. Diene, E. Corvaja, V. Magnano: The use of polyunsaturated phosphatidylcholine in combination with vitamin B complex in the treatment of liver disease. Clin.Ter. 102 (1982) 163-183
11 Watanabe, A., M. Kobayashi, N. Morishita, H. Nagashima: Multimodal treatment resulting in rapid improvement of fatty liver in obese patients. Curr. Therap. Res. 43 (1988) 239-246
12 Knauff, H.G., A. Georgii, K. Matzen: Der Einfluss von Cholinphospholipiden auf das Spektrum der freien Plasmaaminosäuren bei toxischen Leberschäden. Klin. Wochenschr. 41 (1963) 915-919
13 Schüller Perez, A., F. Gonzales San Martin: Placebo controlled study with polyunsaturated phosphatidylcholine in alcoholic steatosis of the liver. Med. Welt 36 (1985) 517-521
14 Gonciarz, Z., P. Besser, E. Lelek, K.J. Gundermann, K.J. Johannes: Randomized placebo controlled double blind trial on essential phospholipids in the treatment of fatty liver associated with diabetes. Med.Chir. Digest 17 (1988) 61-85
15 Kravechenko, A.L.: Effectiveness of the use of the preparation Essentiale in aptients with viral hepatitis. Essentiale Conf. Kiev, Oct. 1981
16 Mudric. V.: Treatment of acute virus hepatitis with Essentiale. Essentiale radovi jugoslavenskih autora, edt. by Bosnalijek/Sarevjevo (1975) 9-14
17 Wallnöfer, H., M. Hanusch: Essential phospholipids in the treatment of hepatic diesease. Med. Wschr. 27 (1973) 93-98
18 Visco, G.: Polyunsaturated phosphatidylcholine in association with vitamin B complex for the treatment of acute viral hepatitis B. Results of a randomized double blind clinical study. Clin. Ter. 114 (1985) 183-188
19 Yano, M., M. Koya, S. Shirahama, T. Toda, Y. Ohta, Ch. Hirayama: Blind assessment of liver biopsy findings in chronic hepatitis: drug efficacy trial of polyenephosphatidylcholine. Shindan to chriyo 9 (1978) 1783-1789
20 Pogromov, A.P., L.I.Otbinskaya, N.I. Antonenko, N.P. Gitel, A. Smolyanitsky, P.B. Verkhovskaya: Use of Essentiale in the treatment of liver diseases. Klin.med. (Moscow) 10 (1978) 97-101
21 Kalab, M., J. Cervinka: Essential phospholipids in the treatment of cirrhosis of the liver. Cas. Lek. ces. 122 (1983) 266-269
22 Fassati, P., J. Horejsi, M. Fassati, Z. Jezkova, J. Spizek: The effect of essential choline phospholipids on HBsAg and on certain biochemical tests in cirrhosis of the liver. Cas.Lek. ces. 120 (1981) 56-60
23 Salvioli, G., R. Lugli: Farmaci che influenzano la secrezione lipidica billiare. Epat. 28 (1982) 11-29
24 Holan, K.R., R.T. Holzbach, J.Y.K. Hsieh, D.K. Welch, J.G. Turcotte: Effect of oral administration of essential phospholipid, Beta-glycerophosphate, and linoleic acid on biliary lipids in patients with cholelithiasis. Digestion 19 (1979) 251-258
25 Toouli, J., P. Jablonski, J.McK. Watts: Gallstone dissolution in man using cholic acid and lecithin. Lancet II (1975) 1124-1126
26 Stiehl, A. , P.Czygan, R. Gtz, R. Raedsch, W. Fröhling: Der Einfluss essentieller Phospholipide auf Gallezusammensetzung und Darmtätigkeit während der Behandlung mit Chenodeoxycholsäure. Verhandlungen der Deutschen Gesellschaft für Innere Medizin (B. Schlegel,Ed.) J.F. Bermann Press, München (1978) 1105-1106