Transcript Training Carnitine - Overview

Carnitor
Training Session India
ST International Department
Carnitine movie
The essential role of Carnitine
• Fatty acid transport
• Detoxification of potentially toxic metabolites
• Regulation of the mitochondrial acyl-CoA/CoA ratio
• Stabilization of cell membranes
Fatty acid transport
• Transport of long-chain fatty acids across the inner
mitochondrial membrane
• Carnitine is the only transporter
• Beta Oxidation – Krebs Cycle – Resp. Chain – ATP
• Carnitine dependent transport of long fatty acids
performed by the enzymes:
Carnitine palmitoyltransferase I
Carnitine–acylcarnitine translocase
Carnitine palmitoyltransferase II
Detoxification of potentially toxic metabolites
•
Carnitine is key in the transport of acyl-CoA compounds accumulated
within the mitochondria
•
Metabolic disorders: amino acids, short & medium chain acyl CoA
accumulates
•
Carnitine mediates transport of partially oxidized fatty acids and amino
acid fragments out of the organelles in the form of acylcarnitines
•
Carnitine prevents the acculmulation of acyl-CoA, a surfactant, which
destabilizes mitochondrial membranes
•
Drugs are conjugated with pivalic or valproic acid and metabolized to
acyl-CoA esters – cytotoxic
•
Increased elimination of acylcarnitines: increasd consumption of Carnitine
Regulation of the mitochondrial Acyl-CoA/
CoA ratio
• Free CoA is an esssential element in the cell’s metabolic
pathsways, cell membranes are impermeable to CoA
• Carnitine controlls intracelluluar concentrations of acyl-CoA,
acetyl-CoA and free CoA: reversible transforamtion of acylCoA and acetyl-CoA into acyl-Carnitine and acetyl-Carnitine,
reactions which produde free CoA
• Free CoA regulates pyruvate dehydrogenase and of the betaoxidation dehydrogenases, which control the supply of acetylCoA for the Krebs cycle
Regulation of the mitochondrial Acyl-CoA/
CoA ratio
Ketogenesis
Results of high rates of fatty acid oxidation: high amounts of
acetyl-CoA are generated, Krebs cycle is saturated, Formation
of ketone bodies
Results of a low or deficient carbohydrate metabolism:
oxaloacetate is low leads to reduced ATP production,
increased keton bodies formation – “The glucose sparing
effect”
Carnitine has a direct control over the rate of production of acetylCoA
Stabilization of cell mebranes
• Carnitine has a stabilizing effect on cell mebranes
• Regulates the turnover of the fatty acids within the
phospholipid membranes
• The availability of free CoA is of paramount importance
for the activation of free fatty acids as acyl-CoA.
• CPT I controls the reacylation of phospholipids
• Carnetine regulates the cellular acyl-CoA/free CoA
ratio
Carnitine Deficiencies
•
Primary deficiency: a genetic defect in the transport of Carnitine across
the cell membrane: OCTN2
•
Secondary deficiencies:
– Inborm errors of Metabolism
• Organic acidurias –amino acid oxidation errors
• Fatty acid oxidation defects
– Carnetine system enzyme defects
– Beta oxidation defects
– Mitochondrial respiratory chain enzyme defects
– Drug-induced Carnetine deficiency
– Physiopathologically-induced Carnitine deficiency
• Total Parenteral Nutrition
• Haemodyalisi
• Myocardial Infarction
Carnitine movie
Mitochondrial carnitine pathway
interplay between lipid and glucose metabolism
Background
1905 Carnitine is isolated from muscle tissue
1952 Stimulation of fatty acid oxidation
1973 Congenital carnitine metabolism disorders are
discovered
1995 Carnitine’s role in acyl-group transfer is recognised
2003 New indications
Chemical structure
CH3
H3C
N+
H
_
CH2
CH3
CH2
OH
acetyl
proprionyl
palmitoyl
C
C CH3
O
C CH2CH3
O
C (CH2)14CH3
O
COO
Chemistry
Chemical formula:
C7H15O3N
Molecular weight:
161
Appearance:
White powder
Solubility:
Highly soluble in acetone
In the organism
The concentration in the tissues depends on the type of
metabolism (lipid or glucose).
The highest concentration is found in the skeletal muscle
and heart.
The following highest concentrations are found in
adipose tissue, the liver and adrenal cortex.
In the organism
The total amount of carnitine contained in the body is
between 15 and 20 g.
More than 95% of which is located in the skeletal muscle
and heart.
Distribution within the body
Body liquid/tissues
L-carnitine
content
L-carnitine
total amount
nmol / g
mg
%
1,100 – 3,900
19000
96
600 – 1,200
~ 60
0.30
Liver
600 – 1,000
~ 300
1.50
Kidney
300 –
600
~ 150
0.75
Brain
500 – 1,000
~ 250
1.25
60
~ 50
0.25
8,000 – 12,000
~ 20
0.10
Muscle
Heart
Blood
Epididymes
40 –
Pharmacokinetics
In metabolically healthy adults, 25 to 35% of normal
carnitine requirements are satisfied by endogenous
synthesis, the remainder by foods of animal origin.
The primary reabsorption of L-carnitine in the small
intestine is caused partly by an active and saturable
mechanism and partly by a passive, concentrationdependent process.
Sources
Endogenous
synthesis
Diet
15 - 20 mg/day
2 - 100 mg/day
L-carnitine content
of foods (mg/100 g)
Mutton
203.0
Where?
Beef
61.0
In the liver and
kidney
Pork
27.0
Sheep’s milk
14.0
Cow’s milk
2.6
Eggs
0.8
Rice
1.8
Bread
0.5
Potatoes
0.05
Carrots
0.0
Cabbage
0.0
From what?
The amino acids
lysine and
methionine
Cofactors?
Vitamins B6, Niacin,
Vitamin C, and iron
Pharmacokinetics
The primary oral bioavailability for therapeutic doses is
10 to 18%.
The free carnitine normal values are:
–
Serum/Plasma: 32-48 µmol/l (free + acyl-carnitine: 39-68
µmol/l);
–
Muscle: 24 µmol/g of non-collagen protein;
–
Myocardium: 6.5-10 µmol/g of non-collagen protein;
–
Urine: 80-200 µmol/24 h.;
–
Erythrocytes: 0.1 µmol/g.
Excretion
The excretion of free and acyl-carnitine is primarily renal.
Long-chain acylcarnitine is excreted far more rapidly than
free carnitine.
Excretion
Free carnitine clearance is dose-dependant. For poor
intakes (e.g. in vegetarians) it is lower due to higher
reabsorption.
Conversely, in healthy adults, it increases with the
therapeutic dose.
Mitochondrial carnitine pathway
interplay between lipid and glucose metabolism
Acyl-CoA-Synthetase
Acyl-CoA-Synthetase
Long-chain fatty acids (>12 C) are extracted from triglycerides
by an intravascular or intracellular lipase which is then
activated by Acyl-CoA Synthetase, located in the outer
mitochondrial membrane (and in the microsomes).
Carnitine Palmitoyl-Transferase
Carnitine
Acyl-CoA
CPT
There are 2 sub-groups :
• CPT I is found on the outside face of the mitocondrial membrane.
• CPT II is located on the matrix side.
CPT and I CPT II have a vast specificity for the medium- to
long-chain acyl groups
CPT
CPT I and II catalyse the reversible transfer of activated fatty
acids between CoA and L-carnitine.
Acyl CoA +
L-carnitine
CPT I
CPT II
CoA +
Acyl-L-carnitine
Acylcarnitine
Acylcarnitine acts as an energy reservoir for storing and
transporting the temporarily excessive acyl groups caused by
a reduction in fat deposits.
Carnitine Translocase
Carnitine Translocase
The transportation of carnitine or acylcarnitine through the
mitochondrial membrane is catalysed by an exchange
system, carnitine translocase (CT).
Carnitine Palmitoyltransferase II
Energy production
ß-Oxidation
Kreb‘s
cycle
Electron transport
chain
ATP
Carnitine Acetyltransferase
Carnitine Acetyltransferase
Carnitine acetyltransferase re-binds the acetyl group of
acetyl-CoA to carnitine, to produce acetyl-carnitine and free
CoA, which can once more integrate the Kreb’s cycle.
Carnitine Translocase
The carnitine system
AcylCoA
CARNITINE
CPT
1
C
T
CPT
2
C
T
Mitochondrial carnitine pathway
interplay between lipid and glucose metabolism
Topics
• Carnitine: overview on its metabolic role in health and disease
• Carnitine biosynthesis, metabolism and functions
• Carnitine deficiency: primary and secondary
• Dialysis
• Drug induced deficiency
• Sigma-tau carnitines
Primary Carnitine Deficiency (PCD):
pathophysiology
•PCD is caused by a deficiency in the plasma membrane OCTN2 carnitine
transporter expressed in muscle, heart, kidney, lymphoblasts and
fibroblasts, with restricted tissue uptake and urinary carnitine wasting
causing systemic carnitine depletion.
•Intracellular carnitine deficiency impairs the entry of long-chain fatty acids
into the mitochondrial matrix.
•Consequently, long-chain fatty acids are not available for beta-oxidation
and energy production, and the production of ketone bodies (which are
used by the brain) is also impaired.
http://emedicine.medscape.com/article/942233-overview
Rebouche CJ, 2005. Encyclopedia of Dietary Supplements
Primary Carnitine Deficiency (PCD):
pathophysiology
•
Plasma membrane OCTN2 carnitine transporter defect is caused by a
rare autosomal recessive error of the gene SLC22A5 (located on
chromosome 5q31)
•
The genetic deficiency of the transporter activity represents the only
known form of PCD.
PCD: epidemiology
•In a Japanese study, primary systemic carnitine deficiency was estimated to
occur in 1 per 40,000 births.
•No incidence studies in the United States. However it may be similar to the
incidence in Japan from the cases already reported
•In Australia, the incidence has been estimated to be between 1:37,0001:100,000 newborns.
•The frequency of this condition in adults is not known. However, in the
United Kingdom, a previous report identified 4 affected mothers in 62,004
infants screened, with a frequency of 1:15,500.
•Of particular interest is the population of the Faroe Islands, in which the
condition is found in about 1 in every 500 people.
http://emedicine.medscape.com/article/942233-overview
http://www.cphpost.dk/news/135-science/48995-faeroes-susceptible-to-deadly-illness.html
PCD: different forms
Depending on the time of onset there are three distinct clinical entities:
•the adult
•the infantile
•the perinatale
Differences in severity/onset of the disease are due to different mutations in
SLC22A5
Flanagan et al., Nutrition and Metabolism 2010, 7:30
PCD: different forms
Depending on the system involved there are two forms:
• The systemic form, caused by malabsorption of carnitine in the
gastrointestinal tract, shows low carnitine in the liver and/or plasma.
• The myopathic form, restricted to skeletal muscle, is caused by
difficulties in carnitine‘s penetration of muscle cells. Lipid storage
myopathy occurs with low muscle carnitine but normal liver and serum
carnitine.
Both forms cause severe lipid metabolism alterations with lipid storage
myopathies and problems in cardiac and skeletal muscle contraction
http://www.ncbi.nlm.nih.gov/omim/212160
PCD
clinical findings
Three tissues/organs are affected in PCD:
•
Cardiac muscle → progressive cardiomyopathy.
Onset may occur with rapidly progressive heart failure or murmur. Cardiomegaly may be
found associated with the presence of a heart murmur. A gallop rhythm can be found,
associated with a dilated cardiomyopathy. Pericardial effusion.
•
Central nervous system → encephalopathy caused by hypoketotic hypoglycaemia.
The patient may present limp, unresponsive, and comatose after a prolonged fast. Pyramidal
movements or minimal athetoid movements can persist. Modest hepatomegaly also can be
appreciated, elevated liver transaminases, and hyperammonemia.
•
Skeletal muscle → Myopathy.
In the myopathic presentation, patients may have mild motor delays, hypotonia, or
progressive proximal weakness.
Other manifestations:
•
•
•
GI dysmotility, with recurrent episodes of abdominal pain and diarrhea
Hypochromic anemia and recurrent infections
Mild developmental delay can be the only manifestation in rare cases
Flanagan et al., Nutrition and Metabolism 2010, 7:30. http://emedicine.medscape.com/article/942233-overview
PCD
clinical findings
http://ods.od.nih.gov/news/carnitine_conference_summary.aspx
Newborn screen
PCD can be identified in infants by expanded newborn screening using tandem
mass spectrometry by detection of low levels of free carnitine (C0)*.
–
Pediatrician needs to contact the family to inform them of the newborn screening
result and ascertain clinical status and whether the newborn presents with poor
feeding, lethargy or tachypnea.
–
Consultation with a pediatric metabolic specialist has to be immediately activated
and the newborn should be evaluated for tachycardia, hepatomegaly, or reduced
muscle tone. After obtaining confirmatory testing with total and free plasma
carnitine levels in the newborn and mother, carnitine supplementation.
*In addition, newborns’ low carnitine levels may result from PCD in their affected mothers or, on the contrary, can be within the
reference range if obtained too early, due to the transfer of carnitine through the placenta to the fetus.
Newborn screen
– Confirmatory and diagnostic testing can be performed with carnitine uptake
assay in cultured fibroblasts and OCTN2 gene sequencing.
– Clinical availability of OCTN2 gene sequencing may preclude the need of a
skin biopsy and carnitine uptake assay on cultured fibroblasts.
– The family has to be educated about signs, symptoms and need for urgent
treatment if infant becomes ill
Laboratory Studies
If the patient is suspected of having PCD and is presenting with a metabolic
emergency, the following studies are indicated:
1.
Immediate assessment: blood glucose and urine ketones if a child
presents to the emergency room with lethargy, seizures, apnea, or any
episode of decreased consciousness.
2.
Ammonia level, liver enzymes, chemistry panel, uric acid, creatine kinase
(CK), lactic acid, and coagulation tests
*LCHAD=long-chain 3-hydroxyacyl-CoA dehydrogenase
http://emedicine.medscape.com/article/942233-overview
Laboratory Studies
3.
Plasma carnitine level: In PCD, the carnitine level in plasma is usually
less than 5% of normal, with acylcarnitines proportionately reduced. The
ratio between acylcarnitine and free carnitine is normal.
4.
Urine carnitine level: the transporter in kidney cells has decreased
capacity for reabsorption, causing increased carnitine excretion.
5.
Fasting test: blood samples at regular intervals to measure glucose,
ketone bodies, free fatty acids and acylcarnitine profile.
Fasting may be continued in children for up to 24 hours, unless blood
glucose drops to less than 3 mmol/L. An inadequate production of
ketones with a high free fatty acid–to–ketone bodies ratio suggests a
defect in long-chain fatty acid oxidation.
Laboratory Studies
6.
Fatty acid oxidation study: This is used if a fatty acid oxidation defect
is suspected. The most appropriate first line of investigation in these
patients is to study the entire fatty acid oxidation pathway.
7.
Enzyme assay: This criterion standard for demonstrating an enzyme
defect measures the activity in cultured fibroblasts or in some other
tissue, such as muscle or liver.
8.
Carnitine transport assay in cultured fibroblasts (skin biopsy)
specifically demonstrates the absence of active carnitine transport in
cultured fibroblasts (specific for PCD).
Laboratory Studies
9. Molecular diagnosis provides information on the gene for the carnitine
transporter defective in PCD, which has been cloned (OCTN2) and can
be screened for mutations.
10. Mutation analysis: the genes for most of the enzymes of fatty acid
oxidation that are defective in fatty acid oxidation disorders and may
cause secondary carnitine deficiency have been identified, and mutation
analysis is available for numerous genes (eg, CPT I, CPT II, VLCAD,
MCAD). For example in the adult form of CPT-II deficiency, a C439T
mutation accounts for 60% of mutations in patients with adult onset.
VLCAD= very long-chain acyl-CoA dehydrogenase
MCAD=medium-chain 3-hydroxyacyl-CoA dehydrogenase
CPT I and II= carnitine palmitoyltransferase I and II
Imaging Studies and other tests
Imaging studies:
•
X-rays reveal cardiac enlargement
•
The echocardiogram may reveal cardiac enlargement and increased
thickness of the left ventricular wall.
•
Brain imaging studies (eg, cranial ultrasound, brain MRI) may show
cystic lesions in glutaric aciduria type II or basal ganglia involvement in
mitochondrial disorders that may be associated with secondary carnitine
deficiency.
Other tests:
ECG: The ECG reveals left ventricular hypertrophy and peaked T waves
in primary carnitine deficiency. Cardiac arrhythmias can be observed in
translocase deficiency and in the lethal neonatal form of carnitine
palmitoyltransferase II (CPT-II) deficiency.
Therapy
•
In infants with carnitine deficiency oral L-carnitine supplementation is a
lifesaving treatment.
•
Use of L-carnitine in PCD restores plasma carnitine levels to nearly normal.
•
Cardiomyopathy often responds well to carnitine supplementation.
•
Carnitine supplementation in fatty acid oxidation disorders and other
organic acidurias is to correct carnitine deficiency and to allow removal of
toxic intermediates.
•
The other goal of therapy is to restore CoA levels.
•
Carnitine supplementation in total parenteral nutrition (TPN) prevents
secondary carnitine deficiency in preterm newborns.
http://emedicine.medscape.com/article/942233-overview
PCD Therapy: L-carnitine dosing
Pediatric
•
50 mg/kg/d PO initially; may gradually increase to 100-400 mg/kg/d PO
divided bid/tid; not to exceed 3 g/d
Adult
•
1 g PO/IV tid; not to exceed 3 g/d
L-carnitine therapy will need to be continued for life
http://emedicine.medscape.com/article/942233-overview
Thomson Pharma Drug Report, 2010. Thomson Reuters
L-carnitine therapy:
left ventricular dimensions
http://ods.od.nih.gov/news/carnitine_conference_summary.aspx
SCD: patophisiology
•
SCD can be caused mainly by :
inherited metabolic disorders [eg organic acidurias, FA oxidation
defects, (carnitine system enzyme defects, β-oxidation defects,
respiratory chain enzime defects)]
acquired medical conditions (eg haemodialysis, peritoneal dialysis)
iatrogenic states (eg drug induced carnitine deficiency)
or other factors like poor diet or malabsorption of carnitine or increased renal
tubular loss of free carnitine (Fanconi syndrome),
SCD: patophisiology
•
SCD is characterized by increased carnitine excretion in urine in the form
of acyl-carnitine due to an accumulation of organic acids
•
At least 15 syndromes in which carnitine deficiency seems to be
secondary to genetic defects of intermediary metabolism or to other
conditions
•
SCD is less severe than PCD with respect to its short-term clinical impact
and is much more common
SCD: clinical findings
• Breastfed infants may experience a catabolic state shortly after birth, when
the production of milk is not adequate to meet nutritional requirements.
• Acute metabolic decompensation with hypoketotic or nonketotic
hypoglycemia usually occurs in infancy, whereas cardiac and skeletal
muscle disease manifest later. Patients may have a history of developmental
delay.
• Patients with organic acidemias causing secondary carnitine deficiency may
present with crises consisting of hypoglycemia, ketoacidosis, and
hyperammonemia.
• Carnitine deficiency has been observed in children with urea cycle defects,
and it may exacerbate episodes of hyperammonemia.
• Signs and symptoms related to carnitine deficiency are not completely defined
in the newborn. Apnea, cardiac death, and sudden death have been found in
infants with carnitine depletion.
SCD: clinical findings
•
Episodes of metabolic decompensation triggered by infection or fasting may
present with lethargy that may be accompanied by seizures or apnea.
•
This encephalopathy may also present with hypotonia and hepatomegaly.
•
Signs of cardiac hypertrophy may be evident, with gallop or heart murmur on the
cardiac examination.
•
Less frequently, these patients may have other findings, such as pigmentary
retinopathy, peripheral neuropathy, cardiac arrhythmias, or myoglobinuria.
•
Carnitine deficiency can develop in children with renal Fanconi tubulopathy; it
may be idiopathic and present with renal tubular acidosis or secondary to
acquired or inherited conditions.
Therapy
Administration of carnitine improves clinical evolution and
reduces the frequency of metabolic attacks.
SCD Therapy: Pediatric dosing
• Initial:
-50 mg/kg IV bolus (over 2 to 3 min) or infusion; repeat 50 mg/kg IV daily if
clinically indicated; max dose 300 mg/kg
-50 mg/kg orally in divided doses daily, titrate slowly to therapeutic response;
max dose 3 g daily
• Severe metabolic crisis, initial, 50 mg/kg IV over 2 to 3 min bolus injection or
infusion, repeat 50 mg/kg IV in divided dose over 24 hr (every 3 to 4 hr and not
less than every 6 hr); repeat 50 mg/kg IV daily if clinically indicated; MAX dose
300 mg/kg
Thomson Pharma Drug Report, 2010. Thomson Reuters
SCD Therapy: adult dosing
• Initial, 50 mg/kg IV bolus (over 2 to 3 min) or infusion; repeat 50 mg/kg IV daily if
clinically indicated; MAX dose 300 mg/kg
• Severe metabolic crisis, initial, 50 mg/kg IV over 2 to 3 min bolus injection or
infusion, repeat 50 mg/kg IV in divided dose over 24 hr (every 3 to 4 hr and not
less than every 6 hr); repeat 50 mg/kg IV daily if clinically indicated; MAX dose
300 mg/kg
• Tablet, 1 g ORALLY 2 to 3 times daily
• Oral solution, initial, 1 g orally daily, titrate slowly to therapeutic response;
average dose 1 to 3 g orally daily for 50 kg adult
Thomson Pharma Drug Report, 2010. Thomson Reuters
Secondary genetic carnitine deficiency
• CPT-I deficiency Carnitine palmitoyltransferase 1
• CPT-II deficiency Carnitine palmitoyltransferase 2
Secondary genetic carnitine deficiency
CPT-I deficiency
•
Carnitine palmitoyltransferase I (CPTI) deficiency is thought to cause
serious disorders of fatty acid metabolism.
•
The nucleotide sequences of cDNA and genomic DNA encoding human
CPTI have been characterized
•
However, a relationship between disease and mutation of the human
CPTI gene has not been reported
Secondary genetic carnitine deficiency
CPT II deficiency
•
The adult CPT II clinical phenotype is somewhat benign and requires
additional external triggers such as high intensity exercise before the
predominantly myopathic symptoms are elicited.
•
The perinatal and infantile forms involve multiple organ systems.
•
The perinatal disease is the most severe form and is invariably fatal.
Secondary genetic carnitine deficiency
CPT II deficiency
•
The most frequent symptom of muscle palmitoyltransferase CPT II
deficiency is an exercise induced myalgia.
•
Myoglobinuria, is the traditional hallmark of this disease
•
Myalgia typically starts in childhood while myoglobinuria starts later in
adolescence or early adulthood.
Secondary genetic carnitine deficiency
CPT II deficiency
•
One case study found a novel mutation in CPT II (del1737C), an
autosomal recessive disease with a distinct phenotype. A two- day old
boy died due to severe hepatocardiomuscular disease with an extreme
early onset. His sister also died. Upon autopsy the brother showed
massive pulmonary atelectasis with intra-alveolar hemorrhage, cardioand hepato-megaly. The sister died of sudden cardiopulmonary arrest
due to the increase of long-chain (C16-18) acylcarnitines. Decreased
CPT II activity was found in her liver, heart and kidney.
The cause of death was neonatal CPT II deficiency.
Topics
• Carnitine: overview on its metabolic role in health and disease
• Carnitine biosynthesis, metabolism and functions
• Carnitine deficiency: primary and secondary
• Dialysis
• Drug induced deficiency
• Sigma-tau carnitines
DIALYSIS
Dialysis
Severe kidney failure is still a serious health problem.
The greatest problems for patients are the kidney failure
itself and the side effects of dialysis.
Post-dialysis syndrome
Symptoms
• Chronic fatigue
• Impaired performance
• Low cardiac output
• Poor state of nutrition
• Hypotension during dialysis
• Muscle pains and/or cramps during dialysis
L-carnitine effects on skeletal muscle
in hemodialysed patients
Dialysis
Haemodialysis extracts carnitine directly from the “fast
equilibrating pool” (blood and liver).
After a dialysis session, the plasma carnitine concentration
normalises through the mobilisation of carnitine from the
“slow equilibrating pool” towards the “fast equilibrating
pool”.
Dialysis
The consequence of this process is a loss of carnitine from
the “slow equilibrating pool“ and the onset of secondary
carnitine deficiency.
Post-dialysis carnitine supplementation compensates this
loss in the “fast equilibrating pool“ and reduces the loss in
the “slow equilibrating pool“.
Dialysis
The plasma levels of free carnitine at the end of a dialysis
session must not be below the threshold of 40 µmol/l.
To maintain this level, plasma concentrations prior to
dialysis must be within the 120 - 150 µmol/l range.
Dialysis and anaemia
Anaemia represents one of the greatest problems for
dialysis patients.
L-carnitine alters red blood cell deformability.
L-carnitine administration reduces erythropoietin
requirements in about 45% of patients.
Carnitine therapy
Administration of carnitine :
• increases plasma and muscle carnitine levels.
• improves tolerance of exertion.
• reduces intradialytic muscle cramps and hypotension.
• improves cardiac function.
Carnitine therapy
• improves general clinical condition.
• improves quality of life.
• improves serum markers related with nutrition: it
increases albumin and reduces urea and creatinine.
• improves erythropoietin-resistant anaemia.
Therapeutic applications
In dialysed patients, L-carnitine helps to compensate
the loss of carnitine and prevents the onset of postdialysis syndrome.
L-carnitine is consequently indispensable for the
treatment of these patients.
L-Carnitine and renal anaemia
Improvement in haematocrit
Source: Trovato et al.
Current Therapeutic Research1982
L-Carnitine and renal anaemia
Reduced rh-EPO levels
Source: Veséla et al.
Nephron 2001
Reduction in Rh-EPO levels whilst
taking L-Carnitine
a) Kavadias et al. EDTA Congress 1995
b) Labonia et al. American Journal of Kidney Diseases, 1995
c) Boran et al.
d) Patrikarea et al.
Nephron, 1996
EDTA Congress 1996
Therapy-dialisys
Pediatric and Adult
SCD- Treatment and Prophylaxis - End stage renal disease - Hemodialysis
•
initial, 10 to 20 mg/kg (dry weight) over 2 to 3 min bolus injection after dialysis; subsequent dose
titration determined by trough (predialysis) levocarnitine concentrations (Prod Info CARNITOR(R)
injection, 2004)
Thomson Pharma Drug Report, 2010. Thomson Reuters
Topics
• Carnitine: overview on its metabolic role in health and disease
• Carnitine biosynthesis, metabolism and functions
• Carnitine deficiency: primary and secondary
• Dialysis
• Drug induced deficiency
• Sigma-tau carnitines
Valproic acid intoxication
Valproic acid
Most patients on valproate treatment have low plasma
carnitine levels.
An even greater reduction is observed in patients on
valproate therapy who are simultaneously taking
supplementary antiepileptic medication.
Valproic acid
Valproate (Depakine®) is an antiepileptic medication.
This illness often requires long-term therapy and in addition to
valproate, patients are often taking other substances.
Patients on valproate medication experience more consistent
reductions in acylcarnitine and a higher proportion of acylcarnitine to
free carnitine.
Carnitine deficiency may present in children being treated with valproic
acid and may be associated with fulminant liver failure and presentation
similar to that in Reye syndrome. It also may present with a myopathy
and increased lipid storage in patients with AIDS who are being treated
with zidovudine.
Valproic acid
Treatment with carnitine can block a tendency to
hyperammonaemia and hypocarnitinaemia and result in an
improvement in terms of carnitine and greater acylcarnitine
clearance without reducing the effects.
Carnitine supplements also eliminate toxic acyl CoA as
acylcarnitine.
Topics
• Carnitine: overview on its metabolic role in health and disease
• Carnitine biosynthesis, metabolism and functions
• Carnitine deficiency: primary and secondary
• Dialysis
• Drug induced deficiency
• Sigma-tau carnitines
Sigma-tau Carnitines: know-how
•
In 1977 sigma-tau synthesizes the biologically active L-carnitine
•
In 1978 sigma-tau is the first inventor of L-Carnitine industrial production process
(Italian Patent no.1156852)
•
First launched in 1982 in Italy
•
US FDA Orphan Drug designation in 1985* (primary deficit) followed by those in
1992 (secondary deficit) and in 1999 (dialysis deficit)
•
A wide library on carnitines present in sigma-tau
*second Orphan Drug Designation awarded by US FDA
Sigma-tau Carnitines
Three active ingredients:
• L-Carnitine (LC)
• Acetyl L-Carnitine (ALC)
• Propionyl L-Carnitine (PLC)
Three product families
Sigma-tau Carnitines
Three presentations:
• End Products
• API
• Nutraceuticals containing Carnitines
Three forms requested by the MKT
Sigma-tau Carnitines:
End Products
REGION
North America
Central/South America
COUNTRY
Product
name
USA
Carnitor
CANADA
Carnitor
COSTA RICA
Cardispan
GUATEMALA
Cardispan
HONDURAS
Cardispan
MEXICO
Cardispan
NICARAGUA
Cardispan
PANAMA
Cardispan
ARGENTINA
Albicar
CHILE
Carnicor
COLOMBIA
Carnitene
ECUADOR
Carnitine
VENEZUELA
Carnitene
ALBANIA
Carnitene
L-Carnitine
Fresenius
Carnitene
L-Carnitin
"Fresenius"
Levocarnil
AUSTRIA
BELGIUM
CZECH REPUBLIC
FRANCE
37 country registrations
12 Brands
GERMANY
L-Carn
GREECE
Superamin
Carnitene
Sigma-Tau
HOLLAND
Europe
ITALY
Carnitene
Nicetile Dromos
MALTA
Carnitene
PORTUGAL
Disocor
SPAIN
Carnicor
Carnitene
Sigma-Tau
SWITZERLAND
A wide diffusion
Asia
Middle East
UNITED KINGDOM
Carnitor
HONG KONG
Carnitor
INDIA
Carnitor
KOREA
L-Carn
PEOPLE'S REP. OF
CHINA
Carnitene
PHILIPPINES
Carnicor
RUSSIAN FED.
Carnitene
TAIWAN
Carnitene
AZERBAIJAN
Carnitene
ISRAEL
Carnitine
TURKEY
Carnitene
Sales: End Products in Units
END PRODUCTS BASED ON: Units 2009
L-CARNITINE
ACETYL L-CARNITINE
PROPIONYL L-CARNITINE
TOTAL
Relevant revenues
4.944.415
1.277.693
268.981
6.491.089
Units 2008
4.735.636
1.224.602
280.358
6.240.596
+-%
4
4
-4
4
Total 2009 turnover
for ST: 56 mio €
Internal data
€
ST Carnitines Trend: End Products (Units)
7,0
6,0
6,0
6,2
6,5
5,5
5,0
4,7
4,0
Units (mio)
3,0
2,0
1,0
0,0
2005
2006
2007
2008
2009
A positive trend since several years
Internal data
Sales: API (Kg)
API
L-Carnitine
Acetyl L-Carnitine
TOTAL
Relevant revenues
Kg 2009
34.885
36.000
70.885
Kg 2008
29.850
32.550
62.400
+-%
17
11
14
Total 2009 turnover
For ST: 8,9 mio €
Internal data
Nutraceuticals containing Carnitines
PRODUCT NAME
ITALY
SWITZERLAND
ITALY
2 AMEDIAL
AZERBAIJAN
BELGIUM
BULGARIA
HOLLAND
ITALY
PAKISTAN
PERU
POLAND
3 PROXEED_plus
SAUDI ARABIA
SERBIA
SINGAPORE
TUNISIA
TURKEY
UK
UNITED ARAB EMIRATES
USA
ITALY
4 CARNIDYN plus
AZERBAIJAN
ITALY
LIBIA
5 EZEREX
PAKISTAN
POLAND
SERBIA
AZERBAIJAN
BELGIUM
6 BIO-RECORD PLUS
HOLLAND
ITALY
AZERBAIJAN
BELGIUM
HOLLAND
HUNGARY
7 PHOTOTROP
ITALY
POLAND
SERBIA
US
ITALY
8 AVANT
ITALY
9 RIABYLEX
ITALY
10 RESTORFAST
ITALY
11 CARNIFAST
US
12 ALCAR
1 CARNIDYN
19 country registrations
12 Brands
A wide diffusion
COUNTRY
Sales: Nutraceuticals containing Carnitines
API
L-Carnitine (LC)
Acetyl L-Carnitine
Propionyl L-Carnitine (PLC)
Both LC and PLC
TOTAL
Relevant revenues
Un. 2009
420.815
797.976
115.889
112.193
1.446.873
Un. 2008
279.352
703.019
68.024
74.368
1.124.763
+-%
51
14
70
51
29
Total 2009 turnover
For ST: 16,1 mio €
Internal data
Sigma-tau Carnitines:
Total 2009 business
• L-Carnitine (LC)
• Acetyl L-Carnitine (ALC)
• Propionyl L-Carnitine (PLC)
81 mio €
A very important business
Internal data
Carnitene®: key facts
Carnitene®
Product name
Active ingredient
L-Carnitine
ATC
A16A other metabolic products - C1X all other cardiac preps
Reference market
A16A other metabolic products - C1X all other cardiac preps
Indications
Primary and secondary carnitine deficiencies
Formulations (packs)
1g/5mL solution for injection-5 ampoules of 5 ml
2g/5mL solution for injection-5 ampoules of 5 ml
1g/10mL oral solution-10 vials of 10 mL
2g/10mL oral solution-10 vials of 10 mL
1g chewable tablets-10 tabs in blister
1,5g/5mL oral solution-bottle of 20 mL
Daily dosage
Oral: Primary carnitine deficiencies and deficiencies secondary to inborn errors:
adults and over 12 years: 2-4 g (from 0 to12 years: depending on age and body weight)
Secondary deficiency due to haemodialysis: 2-4 g
Injection: Secondary deficiency due to haemodialysis:
2 g at the end of the dialytic session (slow i.v.infusion)
Medical target
Pediatrician, Nefrologist, Cardiologist
Registered in (date of first reg.)
Europe (1969), America, Asia
Legal classification
Inj.forms : Rx only;
Oral forms: no subject to medical prescription
Carnitene®: Top down Targeting
KOL
in Pediatrics
Pediatricians,
Nephrologists
Cardiologists,
Geriatricians
Other specialists and GPs
Carnitor® in UK:
an example of sigma-tau L-carnitine Country registration
C O UN T R Y
D is t ribut o r
P ro duc t
na m e
F o rm ula t io ns
1s t re g.
O ra l s ingle do s e 1g
T a ble t s 1g
T a ble t s 3 3 0 m g
19 9 3
19 9 4
19 9 0
Indic a t e d in t he t re a t m e nt o f prim a ry a nd
s e c o nda ry c a rnit ine de f ic ie nc y in a dult s
a nd c hildre n o v e r 12 ye a rs o f a ge .
19 9 2
Indic a t e d in t he t re a t m e nt o f prim a ry a nd
s e c o nda ry c a rnit ine de f ic ie nc y in a dult s
a nd c hildre n up t o 12 ye a rs o f a ge , inf a nt
a nd ne w- bo rns
19 9 4
Indic a t e d in t he t re a t m e nt o f prim a ry a nd
s e c o nda ry c a rnit ine de f ic ie nc y in a dult s ,
c hildre n, inf a nt s a nd ne o na t e s . S e c o nda ry
c a rnit ine de f ic ie nc y in ha e m o dia lys is
pa t ie nt s . Seco ndary carnitine deficiency sho uld be
suspected in lo ng-term haemo dialysis patients who
have the fo llo wing co nditio ns:
1) Severe and persistent muscle cramps and/o r
hypo tensive episo des during dialysis.
2) Lack o f energy causing a significant negative effect
o n the quality o f life.
3) Skeletal muscle weakness and/o r myo pathy.
4) Cardio myo pathy.
5) A nemia o r uremia unrespo nsive to o r requiring
large do ses o f erythro po ietin.
6) M uscle mass lo ss caused by malnutritio n.
3 0 % P a e dia t ric s o l.
UN IT E D
KIN G D O M
S - T P ha rm a Lt d
C a rnit o r
Inje c t io n 1g
Indic a t io ns
Carnitene® in Italy : formulations and turnover
Sell-in €
Sell-in UN
Year 2009
Year 2009
(Thousands) (Thousands)
CARNITENE
Vials OS 2G 10 10ML
Vials OS 1G 10 10ML
Inj. 2G 5 5ML
Inj. 1G 5 5ML
Chewable Tabs 1G 10
Drops OS 30% 20ML
804
410
277
42
42
32
2
6.770
3.847
2.085
377
230
224
7
Carnitene® in Italy :
Current Target
Pediatrician, Nefrologist, Cardiologist, Geriatrician
Carnitene® in Italy :
Current Positioning
Pediatrician
Carnitene® is a unique efficacious drug in primary carnitine deficiency
Nephrologists
Carnitene® is efficacious in secondary deficiencies due to haemodialysis.
Carnitene® may reduce erythropoietin resistance in hemodialyzed patients (HD).
Carnitene® is associated with decreased hospital utilization among HD. This results have important
implications for healthcare cost containment.
Cardiologist-Geriatrician
Carnitene® is a unique efficacious drug in asthenia derived from secondary carnitine deficiency eg in the
elderly, in multi drug treated patients, in malnourished or in cardiopathic patients
GPs
Carnitene® is a unique efficacious drug in asthenia derived from secondary carnitine deficiency eg in the
elderly, in multi drug treated patients, in malnourished or in cardiopathic patients