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Hepa-Merz ® Hepatic Encephalopathy. Hepatic Encephalopathy (HE) - Definition Hepatic Encephalopathy (HE) is a –Metabolically induced –Potentially reversible.

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Presentation on theme: "Hepa-Merz ® Hepatic Encephalopathy. Hepatic Encephalopathy (HE) - Definition Hepatic Encephalopathy (HE) is a –Metabolically induced –Potentially reversible."— Presentation transcript:

1 Hepa-Merz ® Hepatic Encephalopathy

2 Hepatic Encephalopathy (HE) - Definition Hepatic Encephalopathy (HE) is a –Metabolically induced –Potentially reversible –Functional disturbance of the brain Occurring with various degrees of severity secondarily –Grade 0-4 Occurring in both acute and chronic liver diseases. –ie. 70% in cirrhotic patient The mainly cause is a metabolic disturbance –eg. Hyperammonemia

3 Cirrhosis origins Hepatic Encephalopathy Chronic liver disease CirrhosisMinimal HEManifest HE(Pre)Coma ~80% of patients with cirrhosis may suffer from Minimal HE ~50% of patients with Minimal HE will progress towards manifest HE within the next 6 months Ref. Schomerus et al., Dig. Dis. Sci., 26, 7: , 1981

4 Hepatic encephalopathy (HE) - Pathogenesis 1. Ammonia 2. Neurotransmitters hypothesis –2.1 Gamma-aminobutyric acid (GABA) –2.2 Catecholamines and false neurotransmitters 3. Aromatic-branched chain amino acid imbalance 4. Short-chain fatty acids 5. Manganese

5 Development of hyperammonemia Ref. H ä ussinger D. und Gerok W. in: Hepatologie (Hrsg. Gerok W. und Blum H.E.), S. 847,1995. Normal stateHemodynamic causesMetabolic causes Urea Glutamine Urea Glutamine Urea Glutamine NH

6 Detoxification of ammonia in the liver  H ä ussinger, D., Biochem. J. 267: 281 – 290, 1990

7 Diagnostic possibilities in HE Evaluation of the clinical picture using West Haven criteria Flicker frequency analysis (critical flicker frequency, CFF) Determination of mental status: –Psychometric tests (e.g. ZVT, LNT, ZST, handwriting) Neurological investigations: –EEG, MRI, Evoked potentials (eg. Asterixis) Differential diagnosis Laboratory diagnostics to identify triggering factors: –Blood count, Transaminases, Venous acid-base status, Urea, Creatinine

8 HE severity according to West Haven criteria HE grade latent / minimal I II III IVComaAbolished Bizarre behavior, delusions Disorientation, somnolence, stupor Slowing, lethargyConspicuous changes in personality, temporal disorientation Changes in personalityImpaired concentration and impaired reaction speed disturbances, tiredness (decreased vigilance) Clinically unremarkable but psychometric tests pathological Clinically unremarkable, but psychometric tests pathological BehaviorState of consciousness Areflexia, loss of tone Hyperreflexia and hypo- reflexia, asterixis, spasms Asterixis, slurred speech Fine-motor impairment Neuromuscular symptoms  Modified from the original in Conn H. O. and Bircher J. in: Hepatic encephalopathy: Syndromes and Therapies, 13-26, 1994

9 Child-Pugh classification of the stages of cirrhosis Number of pointsParameter 213 EncephalopathyGrade 0Grade I/IIGrade III/IV Billirubin (mg/dl) or≤ 22-3>3 Billirubin ( µ mol/l)(≤ 34)(34-51)(>51) Albumin (g/dl)> < 2.8 Prothrombin time (seconds above norm) > 6 or INR< > 2.3  The Child-Turcotte criteria, modified from Pugh.  The points are added to arrive at the Child-Pugh stage: A (5-6 points), B (7-9), or C (10-15).

10 Number Connection Test (NCT) Grade 0 15 – 30 seconds Grade 1 31 – 50 seconds Grade 2 51 – 80 seconds Grade 3 81 – 120 seconds Grade 4 >120 (test cannot be carried out)

11 Critical Flicker Frequency device (CFF) Close correlation between CFF and severity of HE Statistically significant correlation between CFF and psychometric tests Good correlation between CFF and arterial ammonia concentration Results not dependent on patient’s educational level; no training effects

12 Treatment of Hepatic Encephalopathy options Evaluate dietary protein Eliminating or remove precipitating factors Drug therapy – Non-absorbable disaccharides (eg. Lactulose, Lactitol) – L-ornithine-L-aspartate (LOLA) – Branched-chain amino acid (BCAA) – Oral antibiotics – Flumazenil – Probiotics – Zinc Liver transplant

13 Non-absorbable disaccharides Lactulose – Dose: g/d Titrate to achieve 2-3 soft stool per day or stool pH < 6 – Route: oral or enema* (the comparison of efficacy is unclear) – Efficacy: 70-80% – Tolerability: good – Side effects: cramping, diarrhea, flatulence  Ferenci P, Herneth, A, Steindl, P. Semin Liver Dis 1996; 16:329  Conn, HO, et al. Gastroenterology 1977; 72:573

14 Non-absorbable disaccharides Cochrane meta-analysis 2004 –Thirty randomized trials –No effect on mortality; RR 0.41( , 4 trials) –Improvement of HE; RR 0.62 ( , 6 trials) –No improvement of HE; RR 0-92 ( , 2 high quality trials) –No significant difference between lactulose and lactitol on mortality (2 trials) or improvement of HE (4 trials) but lactitol had fewer side effects –Inferior to antibiotics on improvement of HE; RR 1.24 ( ,10 trials)

15 Oral antibiotics ATBTrialsDoseEfficacyAE NeomycinLactulose, Placebo mg/kg/d?, - Ototoxicity and Nephrotoxicity MetronidazoleLactulose, Neomycin 400 mg bid= Peripheral neuropathy VancomycinLactulose250 mg qid= / +none ParamomycinLactulose4 g/d=none RifaximinLactulose, Lactitol 1,200-2,400 mg/d=none  Strauss E, et al. Hepatogastroenterology 1992; 39:542.  Tarao, K, et al. Gut 1990; 31:702.  Bucci, L, Palmieri, GC. Curr Med Res Opin 1993; 13:109.  Williams, R, et al. Eur J Gastroenterol Hepatol 2000; 12:203.

16 Branched-chain amino acid Meta-analysis 2004 –More rapid mental recovery –Unclear result on mortality –All studies were short duration –Should not consider standard treatment  Naylor, CD, et al. A meta- analysis. Gastroenterology 1989; 97:1033

17 Probiotics One RCT, N=97, minimal HE (MHE) Probiotic vs Fermentable fiber vs Placebo Probiotic significant increased the fecal content of non- urease-producing Lactobacillus species, reduce blood ammonia and reverse mHE about 50%

18 Therapeutic principle

19 Introducing (L-ornithine-L-aspartate) ® Hepa-Merz

20 Hepa-Merz ® Granules

21 Hepa-Merz ® Infusion Concentrate

22 Pharmacokinetics L-Ornithine-L-Aspartate is rapidly absorbed and cleavelaged into L-Ornithine and L-Aspartate Elimination half life of each amino acid is short approximately 40 min Bioavailability is 82.2  28% after Infusion or oral administration Some L-Aspartate appear unchanged in the urine.

23 Ornithine Effect of ornithine on urea synthesis: –Substrate of urea synthesis in urea cycle –Activator of carbamoyl phosphate synthetase

24 Aspartate Effect of aspartate on glutamine synthesis –Substrate in glutamine synthesis –Combining of Citrulline to Arginino-Succinate in Urea Cycle

25 Action mechanism of L-ornithine L-aspartate (OA) Activated H ä ussinger, D., Biochem. J. 267: 281 – 290, 1990

26 The role of L-ornithine-L-aspartate (Hepa-Merz ® ) in the treatment of HE (Represent in some of published clinical studies)

27 Clinical data of Infusion  Kircheis G., Nilius R., Held C. et al., Hepatology 25: 1351 – 1360, Day 0Day 7 L-ornithine L-aspartate Placebo Administration of 20 g OA i.v. (5 g/h) Fasting ammonia levels μmol p < 0.02 N= = LOLA 63 = Placebo Lowering of ammonia by OA infusion

28 Clinical data of Infusion  Kircheis G., Nilius R., Held C. et al., Hepatology 25: 1351 – 1360, 1997 Improvement in HE as a result of OA infusion

29 Clinical data of Granules  Stauch S., Kircheis G., Adler G. et al., Hepatology 28: 856 – 864, (1998) Day 0Day 14 L-ornithine L-aspartate Placebo p < 0.01 Administration of 3 x 6 g OA granules Fasting ammonia levels ( µ mol/l) N=66 34 = LOLA 32 = Placebo Lowering of ammonia by OA granules

30 Oral LOLA Vs lactulose Only LOLA group Has better improvement in Mental status NCT Asterixis EEG Decreased of Serum ammonia LOLA versus Lactulose  JL Poo; J Góngora; F Sánchez-Ávila et al. Annals of Hepatology 5(4) 2006: LOLA Lactulose

31 Summary Therapeutic administration of L-ornithine L-aspartate (Hepa-Merz ® ) increases ammonia detoxification in two ways: –Activation of the urea cycle in the liver, through provision of the metabolic substrates ornithine and aspartate. –The substrates ornithine and aspartate promote glutamine formation, thereby stimulating ammonia detoxification via glutamine synthesis in the liver, in the brain, and in muscle.

32 Hepa-Merz ® General Information's

33 Indication of Hepa-Merz For the treatment of hyperammonemia as a result of acute and chronic liver diseases such as –liver cirrhosis, –fatty liver, –hepatitis; Especially for the treatment of incipient disturbances of consciousness (pre-coma) or neurological complications (hepatic encephalopathy)  Product Insert

34 Indications and Dosage Granules: –Treatment in mHE, sHE, HE I, HE II, III –Containing L-ornithine-L-aspartate 3.0g / 5g / Sachet 1-2 Sachets up to 3 times a day (upon severity of symptom) Dissolve granules in 1 glass of water, tea of juice and drink after meal

35 Indications and Dosage Infusion Concentrate: –HE III, HE IV, Pre Coma, Coma –Containing L-ornithine-L-aspartate 5.0g / 10ml / Ampoule –Dosage 1-4 Amp per day Pre-coma and Coma Up to 8 Amp within 24 Hrs depend on the severity of the condition Max infusion Rate = 5 Gm/ Hour Max Conc. = 6 Amp/ 500 ml Infusion solutions to Mix up; Normal saline, Dextrose, Lactate ringer, Sucrose. etc.

36 Toxicology Toxicological tests of L-Ornithine-L-Aspartate on rats and dogs following single and repeated dose of infusion over 4 week gave no effect at level of approx. 1,500 mg/ kg Reproduction studies on mutagenicity found no abnormalities. There is no need to suspect any carcinogenic potential

37 Safety and Tolerability No case of serious adverse drug reaction 5% of mild gastro-intestinal disturbance i.e, (nausea vomiting) with infusion therapy Nausea is occasional occurred on infusion therapy, with vomiting rarely Symptoms are transient and reversible with reduction of dose or rate of infusion Max rate of infusion is 5 gm (1 Amp) of Hepa-Merz® inf. concentrate per hour is recommended

38 Hepa-Merz Contra-indication Due to Hepa-Merz ® mechanism-increase formation of Urea and eliminate by kidney Hepa-Merz ® is not recommended for patient with severe renal function –Severe renal function = Creatinine level > 3 mg / dl

39 None Known Interaction with Other Medications

40 THANK YOU For your attention NEOPHARM CO.,LTD


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