hepa-merz

Hepa-Merz®

Hepatic Encephalopathy

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

Cirrhosis origins Hepatic Encephalopathy

Chronic liver disease

Cirrhosis Minimal HE Manifest 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: 622-30, 1981

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

Development of hyperammonemia

Ref. Häussinger D. und Gerok W. in: Hepatologie (Hrsg. Gerok W. und Blum H.E.), S. 847,1995.

Normal state Hemodynamic causes Metabolic causes

UreaGlutamine

UreaGlutamine

UreaGlutamine

NH +4 NH +

4 NH +4

Detoxification of ammonia in the liver

Häussinger, D., Biochem. J. 267: 281–290, 1990

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

HE severity according to West Haven criteria

HEgradelatent / minimal

I

II

III

IV Coma Abolished

Bizarre behavior, delusions

Disorientation, somnolence,stupor

Slowing, lethargy Conspicuous changes in

personality, temporal

disorientation

Changes in personalityImpaired concentration and impairedreaction 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

Fine-motor impairment

Neuromuscularsymptoms

Modified from the original in Conn H. O. and Bircher J. in: Hepatic encephalopathy: Syndromes and Therapies, 13-26, 1994

Child-Pugh classification of the stages of cirrhosis

Number of pointsParameter

21 3

Encephalopathy Grade 0 Grade I/II Grade III/IV

Billirubin (mg/dl) or ≤ 2 2-3 >3

Billirubin (µmol/l) (≤ 34) (34-51) (>51)

Albumin (g/dl) > 3.5 2.8-3.5 < 2.8

Prothrombin time(seconds above norm)

1-3 4-6 > 6

or INR < 1.7 1.8-2.3 > 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).

Number Connection Test (NCT)

Grade 0 15–30 seconds




Grade 4 >120

(test cannot be carried out)

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

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

Non-absorbable disaccharides

• Lactulose– Dose: 45-90 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

Non-absorbable disaccharides

• Cochrane meta-analysis 2004– Thirty randomized trials– No effect on mortality; RR 0.41(0.02-8.68, 4 trials)– Improvement of HE; RR 0.62 (0.46-0.84, 6 trials)– No improvement of HE; RR 0-92 (0.42-2.04, 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 (1.02-1.50,10 trials)

Oral antibiotics

ATB Trials Dose Efficacy AE

• Neomycin Lactulose,

Placebo

50-100 mg/kg/d ?, - Ototoxicity and

Nephrotoxicity

• Metronidazole Lactulose,

Neomycin

400 mg bid = Peripheral

neuropathy

• Vancomycin Lactulose 250 mg qid = / + none

• Paramomycin Lactulose 4 g/d = none

• Rifaximin Lactulose, 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.

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

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%

Therapeutic principle

Introducing

(L-ornithine-L-aspartate)

®Hepa-Merz

Hepa-Merz® Granules

Hepa-Merz® Infusion Concentrate

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.

Ornithine

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

Aspartate

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

Action mechanism of L-ornithine L-aspartate (OA)

Activated

Häussinger, D., Biochem. J. 267: 281–290, 1990

The role of L-ornithine-L-aspartate (Hepa-Merz®)

in the treatment of HE(Represent in some of published clinical studies)

Clinical data of Infusion

Kircheis G., Nilius R., Held C. et al., Hepatology 25: 1351–1360, 1997

81

64

83

77

40

60

80

100

Day 0 Day 7

L-ornithine L-aspartate

Placebo

Administration of 20 g OA i.v. (5 g/h)F

astin

g am

mon

ia le

vels

μm

ol p < 0.02

N=12663 = LOLA63 = Placebo

Lowering of ammonia by OA infusion

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

Clinical data of Granules

Stauch S., Kircheis G., Adler G. et al., Hepatology 28: 856–864, (1998)

82

52

93

82

40

60

80

100

Day 0 Day 14

L-ornithine L-aspartate

Placebo

p < 0.01

Administration of 3 x 6 g OA granules

Fas

ting

amm

onia

leve

ls (

µm

ol/l)

N=6634 = LOLA32 = Placebo

Lowering of ammonia by OA granules

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: 281-288

LOLA

Lactulose

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.

Hepa-Merz®

General Information's

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

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

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.

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

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

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

• None Known

Interaction with Other Medications

THANK YOU For your attention

NEOPHARM CO.,LTD

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