Aim
1. Objectives
Primary objective:
The aim of the project is to study the pharmacokinetics of therapeutic doses of
paracetamol with specific emphasis on the contributions of the metabolites
(glucuronide, sulphate, cysteine and mercapturate), in patients with spinal
muscular atrophy(SMA), patients with cerebral palsy(CP), and patients with SMA or
CP admitted to the intensive care unit (ICU), in comparison with healthy controls.
Secondary objective:
The secondary aim is to compare the safety of paracetamol in patients with SMA, CP
and patients with SMA or CP admitted to the ICU, with healthy controls. The
investigators would like to assess the influence of age and physiologic covariates
(body weight and inflammation markers) on paracetamol pharmacokinetics.
2. Background Today there are approximately 15.000 patients with neuromuscular
disorders in Denmark. This includes the group of patients with muscular wasting.
SMA is an example of a neuromuscular disease, where the patients have low skeletal
muscle mass. The disease is located in the anterior cells in the spinal cord. This
affects the cells that are supposed to send signals about muscle contraction
through the nerve pathways, and causes muscle wasting. Spinal muscular atrophy is a
hereditary disease caused by a mutation in the Survival Motor Neuron (SMN) 1-gene.
SMN is necessary for normal nerve function in the muscles. The patients with SMA
have a back-up gene called Survival Motor Neuron (SMN) 2-gene. However, most of the
SMN 2-gene cannot be used, because of a missing part in the gene called exon 7.
Spinal muscular atrophy is divided into three different types, based on the child's
motor skills and when the first symptoms appear. Children with SMA type I
experience symptoms within the first six months of life. The children will never
experience to sit by themselves without help. They seldom get older than two years;
even though it depends on how much intensive respiratory care they receive. The
onset of symptoms for children with SMA type II is between 5 and 12 months of age.
They usually get diagnosed before they reach the age of 1-2 years. The children
will be able to sit by themselves, but will not be able to walk and stand without
help. Children with SMA II can get a normal life span. SMA type III is the mildest
form. The onset of the symptoms appears after the child is 18 months of age, and
the child will be able to walk independently. (1) Cerebral palsy (CP) is another
example of a patient group with low muscle weight. CP is caused by a brain damage
which occurs either during foetal life, during birth or in the neonatal period. The
brain damage occurs in connection to premature birth, oxygen deficiency, infections
or blood clots. However, often the specific cause cannot be detected. Every year
180 children with CP are born in Denmark. The disease will not worsen with time,
but the symptoms will change gradually as the child grows up. Incorrect positions
of joints and bones may occur with time.(2) The investigators have experienced that
two patients with SMA II developed acute liver failure, most likely due to
paracetamol toxicity. In line with this a case study from 2011 reported that
patients with myopathies and muscular atrophies might be at increased risk of
toxicity, resulting in acute liver failure, while receiving the recommended dose of
paracetamol.(3) Another two cases with similar stories has been described in boys
with Duchenne Muscular Dystrophy.(4) Children and young adults with low muscle mass
have several risk factors that may increase the susceptibility to paracetamol.
First of all, they have a reduced skeletal muscle mass compared to bodyweight.(5)
Glutathione (GSH) is a low-molecular-weight thiol, consisting of the amino acids
glutamate, cysteine and glycine. Most of the glutathione synthesis occurs in the
liver and it is stored in the majority of cells in the body. It has been suggested
that skeletal muscle has a remarkable GSH synthesizing ability and high activity of
GSH-dependent enzymes. This suggest that skeletal muscle is a major player for the
whole body GSH metabolism.(6) We hypothesize that the patients with spinal muscular
atrophy, has a lower concentration of glutathione compared to healthy subjects, due
to the fact that they have a low skeletal muscle mass. This is relevant because
glutathione detoxifies the oxidative metabolite in the paracetamol metabolism.
Furthermore, there is a tendency that children and young adults with low muscle
mass are malnourished and have a tendency to become critically ill. Several studies
have shown that there may be a correlation between malnutrition, fasting, critical
illness and glutathione deficiency.(7-9) Lastly, paracetamol is relatively
hydrophilic, and the volume of distribution of paracetamol would be further reduced
in patients with low muscle mass, thus increasing plasma levels.(10) Paracetamol is
commonly used to treat mild-to-moderate pain or to reduce opioid exposure, as part
of multimodal analgesia treatment in patients with SMA and CP. In therapeutic
doses, about 90% of paracetamol is conjugated in the liver to nontoxic metabolites
(glucuronides and sulphates). A small portion (approximately 5 -10 %) is conjugated
by cytochrome P450 CYP2E1 to a toxic metabolite, N-acetyl-p-benzo-quinone imin
(NAPQI). This metabolite is further conjugated by glutathione to a neutral
metabolite and excreted in the urine as cysteine and mercapturate metabolites.(11)
In toxic doses, the usual metabolic pathways are overwhelmed; paracetamol is
shunted to the cytochrome P450 pathway, and glutathione stores are depleted.
Cellular injury and hepatic necrosis occur as NAPQI accumulates.(8) The paracetamol
metabolism pathways are slightly different in young children compared to adults. In
young children up to 12 years of age, the glucunoride pathway is deficient. The
sulphate pathway is the dominant conjugation pathway, and the half-time is
prolonged.(12) Patients with low muscle mass may need a lower loading and
maintenance doses of paracetamol. However, since only one of the three metabolic
pathways of paracetamol (i.e the CYP2E1- mediated pathway) is involved in
hepatotoxicity, it is important to explore the separate contributions of the
different metabolic pathways.(13) Elevations of alanine aminotransferase (ALT) in
the bloodstream are measured as a biomarker, regarding to hepatic events and
toxicity. ALT is an enzyme usually found inside the liver cells, however if the
liver is damaged or inflamed, it could be released in to the bloodstream. A
prospective study of ALT elevations in healthy adults receiving therapeutic doses
of paracetamol exists.(14) However, paracetamol kinetics and liver affection has to
our knowledge never been studied in patients with low muscle mass before.
The investigators would like to conduct a prospective study of the safety and toxicity
related to paracetamol treatment in children and young adults with respectively SMA and
CP.
This study will provide new and important knowledge about the potential risk involved
with paracetamol treatment in therapeutic doses in patients with low muscle mass. If the
investigators find that paracetamol in therapeutic doses are toxic in patients with SMA
and CP, the results will be implemented in new national and international guidelines for
treatment of pain in patients with SMA and CP, to prevent acute liver failure and
potential death, thus improving prophylactic care for these patients.