Schaffner
(2006), stated that a pyrogen is a fever producing substance. The most
important pyrogen is the endotoxin produced by the Gram negative bacteria. Some
pyrogens are there, which are not of microbial origin. They are in fact
pharmacological agents, such as bleomycin and coichicines. But it is the
microbial pyrogens that pose a problem to the manufacturers. While many
organisms including live and dead bacteria, fungi, viruses, malarial parasites,
and the bacterial products such as streptococcal exotoxins, staphylococcal
enterotoxin, bacterial endotoxin lipopolysaccharide, and fungal products can
act as pyrogens, it is the Gram negative bacteria produced endotoxin that is
the most significant pyrogen for the manufacturers of injectables. This
endotoxin is the most significant because its lipopolysaccharide component is
very toxic in very small quantities.
(2006), stated that a pyrogen is a fever producing substance. The most
important pyrogen is the endotoxin produced by the Gram negative bacteria. Some
pyrogens are there, which are not of microbial origin. They are in fact
pharmacological agents, such as bleomycin and coichicines. But it is the
microbial pyrogens that pose a problem to the manufacturers. While many
organisms including live and dead bacteria, fungi, viruses, malarial parasites,
and the bacterial products such as streptococcal exotoxins, staphylococcal
enterotoxin, bacterial endotoxin lipopolysaccharide, and fungal products can
act as pyrogens, it is the Gram negative bacteria produced endotoxin that is
the most significant pyrogen for the manufacturers of injectables. This
endotoxin is the most significant because its lipopolysaccharide component is
very toxic in very small quantities.
The Fever Inducing Mechanism:
Endotoxin
pyrogen enters the bloodstream. It binds to Lipopolysaccharide (LPS) binding protein
(LPB). LPB takes it to the reticuloendothelial system (RES). The receptor cells
in the RES are the circulating mononuclear cells. This attachment to the
receptor causes the production of pro inflammatory cytokines. These cytokines
are interleukin-1 (IL-i), interleukin-6 (IL-6), and tumour necrosis factor-a
(TNFa). These factors produce inflammation and fever (Barone, 2009).
pyrogen enters the bloodstream. It binds to Lipopolysaccharide (LPS) binding protein
(LPB). LPB takes it to the reticuloendothelial system (RES). The receptor cells
in the RES are the circulating mononuclear cells. This attachment to the
receptor causes the production of pro inflammatory cytokines. These cytokines
are interleukin-1 (IL-i), interleukin-6 (IL-6), and tumour necrosis factor-a
(TNFa). These factors produce inflammation and fever (Barone, 2009).
Nature of Bacterial Endotoxin
Endotoxin
is present almost everywhere and is very difficult to remove. Its nature and
omnipresence according to Nguyen (2005) is as following:
is present almost everywhere and is very difficult to remove. Its nature and
omnipresence according to Nguyen (2005) is as following:
·
This is a high molecular weight complex molecule.
This is a high molecular weight complex molecule.
·
This comes from the outer cell wall membrane of gram negative bacteria.
This comes from the outer cell wall membrane of gram negative bacteria.
·
The endotoxin is shed by the bacteria as they live, as they multiply and
also after they die and disintegrate.
The endotoxin is shed by the bacteria as they live, as they multiply and
also after they die and disintegrate.
·
So endotoxin may be present in a system in a form associated with live
organisms or unassociated, in a free manner.
So endotoxin may be present in a system in a form associated with live
organisms or unassociated, in a free manner.
·
Endotoxin associated with microorganisms may be removed by microporous
sterilizing filters, But unassociated endotoxin passes through these filters
also. It cannot be destroyed by autoclaving as it is heat stable.
Endotoxin associated with microorganisms may be removed by microporous
sterilizing filters, But unassociated endotoxin passes through these filters
also. It cannot be destroyed by autoclaving as it is heat stable.
·
Endotoxin can be found in food materials, in ground waters, in soil and
in substances. It is found on laboratory glassware, research apparatus, and
water baths. It can be found in all places where moisture may be there.
Endotoxin can be found in food materials, in ground waters, in soil and
in substances. It is found on laboratory glassware, research apparatus, and
water baths. It can be found in all places where moisture may be there.
Chemical Nature of Endotoxin
Rantala
and Vuopio (2009) stated that bacterial endotoxins contain lipid, protein and
carbohydrate. The primary chemical structure is a polysaccharide structure
which is covalently bound to a lipid, called lipid A. Because of this
structure, the bacterial endotoxin is called as lipopolysccharide or LPS.
and Vuopio (2009) stated that bacterial endotoxins contain lipid, protein and
carbohydrate. The primary chemical structure is a polysaccharide structure
which is covalently bound to a lipid, called lipid A. Because of this
structure, the bacterial endotoxin is called as lipopolysccharide or LPS.
The
lipid A part is in the bacterial cell wall. The polysaccharide projects into
the environment. The polysaccharide consists of two parts; a core
oligosaccharide which is connected to Lipid A and a longer oligosaccharide O-
specific chain which is attached to the core. This second oligosaccharide O-
specific chain is the variable part of the molecular structure. The minimum
variable component is the lipid A. Lipid A consists of a disaccharide of
glucosamine. The glucosamine is highly substituted with ester linked and amide
linked long chain fatty acids. Each fatty acid has a backbone of 14 carbon
atoms. Lipid A is responsible for the harmful and useful activities of
endotoxin.
lipid A part is in the bacterial cell wall. The polysaccharide projects into
the environment. The polysaccharide consists of two parts; a core
oligosaccharide which is connected to Lipid A and a longer oligosaccharide O-
specific chain which is attached to the core. This second oligosaccharide O-
specific chain is the variable part of the molecular structure. The minimum
variable component is the lipid A. Lipid A consists of a disaccharide of
glucosamine. The glucosamine is highly substituted with ester linked and amide
linked long chain fatty acids. Each fatty acid has a backbone of 14 carbon
atoms. Lipid A is responsible for the harmful and useful activities of
endotoxin.
