Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5255_Библиотеки_им_академика_М_И_Перельмана
.pdf
232
Substrate non-specific
1. Simple diffusion
2. Exchange diffusion
3. Active transport
4. Phagocytosis
5. Compartmental localization
6. Capillary blockade
7. Cell sequestration
8. Chemisorption
Substrate specific
1. Isotopically substituted biochemical
2. Metabolic trapping
3. Enzyme substrate
4. Receptor binding
5. Antigen-antibody reaction
Substrate non-specific
Radiopharmaceuticals in Clinical Nuclear Medicine
Simple diffusion
Simple diffusion describes a mechanism in which a radiotracer diffuses across cell membranes
and then redistributes itself elsewhere in the body. This mechanism does not require energy.
For example
blood stream. Another example is the uptake of
133
Xe gas diffuses across membranes in the lungs and then circulates in the
99m
TcO4 in the brain due to defect in the
blood brain barrier (transport of radiopharmaceutical along the concentration gradient due
to increased permeability).
Exchange diffusion
The chemical nature of certain elements is such that they have specific locations in the body.
For example, some ions generally exist outside of cells (e.g. sodium) while others exist
inside cells (e.g. potassium). Some elements are principally located within the skeleton (e.g.
calcium). The mechanisms responsible for these distributions can be exploited to introduce
radioactivity into an organ by exchange diffusion. For example, thallium is a chemical
analogue of potassium and enters myocardium by exchange diffusion. The exchange of 18F
with hydroxyl group of amorphous portion of hydroxyapatite is another example of this
mechanism. The exchange process leads to the formation of 18Flouroapatite, which can be
imaged by PET.
GSPant\Newbook\15-chp\232
Radiopharmaceuticals in Clinical Nuclear Medicine
233
Active transport
Active transport involves the use of a normally operative energy-dependent metabolic pathway
in the body to move the radiopharmaceutical across a cell membrane and into the cell
against an electrochemical gradient. The mechanism requires the presence of naturally
occurring transporter protein (on cell membrane) and energy utilization (usually in the form
of ATP). Radiopharmaceuticals, which are structurally analogous to the natural substance
undergoing active transport, are also handled in the similar manner. For example, thyroid
uptake of radioiodine is by active transport. The
with the same mechanism. Some compounds like
99m
Tc-MAG3 and
201
Tl being structural analogue of K
131
I-OIH also localize
localize by active transport as well as by diffusion.
Phagocytosis
Physical entrapment of colloidal particles by macrophages, distributed throughout the reticuloendothelial system (RES), is called phagocytosis. The mechanism critically depends on the
size of the particles, which may be different for different organs. The smaller the particles,
the greater the bone marrow uptake; larger particles tend to localize in the liver and spleen.
Due to the small size of the colloid compared to the diameter of the average capillary (7 µm)
blockade does not occur. Example of a most commonly used colloid in nuclear medicine is
99m
Tc-sulfur colloid in which the particle size ranges from 0.1 to 1m, with a mean size of
0.3 m. Distribution of
spleen, and 5% in marrow. However, in liver dysfunction (chronic liver disease) there is
colloid shift with significant uptake in spleen and bone marrow because of reduced number
of Kupffer cells (macrophage) in liver RES. Colloids of smaller sizes, such as
sulfide, have been used for lymphoscintigraphy.
99m
Tc-Sulfur colloid in RES is typically 85% in the liver, 10% in the
99m
Tc-antimony
+
Compartmental localization
A compartment refers to a single homogeneous well-mixed distinct component of a biological
system. Here it represents a distinct physical fluid space. The tracer is introduced into the
space and maintained for some time for imaging purpose. Introduction of
111
In labeled
DTPA into the subarachnoid space by lumbar puncture and imaging CSF kinetics is one of
the examples of this mechanism. Another example of compartmental localization is blood
pool imaging using autologous
99m
Tc labeled red cells or
within the blood pool or infusion of a dilute solution of
99m
of
Tc- sulfur colloid into the urinary bladder in a voiding cystogram.
99m
99m
Tc Human Serum Albumin
Tc- pertechnetate or a suspension
Cell Sequestration
This mechanism utilizes the normal function of the spleen, which recognizes and traps
damaged erythrocytes. The method involves heat denaturing of a small volume of erythrocytes
GSPant\Newbook\15-chp\233
234
Radiopharmaceuticals in Clinical Nuclear Medicine
and radiolabelling them for imaging. In splenectomised patients, detection of accessory
spleen is best accomplished by this method.
Capillary blockade
It is deliberate microembolisation of capillaries with radiolabelled particles. The amount of
microembolisation is proportional to arterial blood flow to that region. The lung perfusion
imaging with
99m
Tc-MAA (macro albumin aggregate) is good example of this mechanism.
An average of 350,000 particles (range 200,000 to 700,000) with 90% of them with 10-90
m size are injected intravenously. Approximately 600 million pulmonary arterioles are
estimated to be small enough to trap these particles. Thus the physiological effect of the
microembolisation is insignificant. However, in adult patients with pulmonary hypertension,
number of particles is reduced to 150,000.
Chemisorption or physico-chemical adsorption
This is avid and irreversible binding of specific chemical structure onto the tissue surface.
For example,
99m
Tc-diphosphonate, phosphate and diarsonate complexes adsorb onto bone
surface. The structural configuration of the molecule is more important than the presence of
specific atom in the molecule e.g. both diphosphonate (P-C-P) and diarsonate (As-C-As)
adsorb on the bone surface to the same extent. Uptake of diphosphanate (at 3 h) is not due to
bone turn over (which normally takes 3-4 months) but depends on bone surface area available.
For example in rickets, mineralisation is defective but
99m
Tc-diphosphonate uptake is
increased. Increased osteoid formation leads to high surface to volume ratio of bone resulting
in increased adsorption of
99m
Tc-diphosphonate.
Substrate specific
Isotopically substituted biochemicals
This mechanism depends on the substitution of stable atoms of biochemical substances by
radioactive atoms. Radioisotopes of carbon, nitrogen, oxygen and hydrogen can easily
substitute stable atoms/molecules in body organs. All of the currently used radionuclides for
this purpose are positron emitters which are used in PET imaging, the most important
functional imaging modality available today.
Metabolic trapping
An example of metabolic trapping is
organs immediately after intravenous injection, it is excreted out except from brain and
heart where it is retained for a long time. Unlike glucose, it does not undergo renal tubular
reabsorption and follows rapid renal excretion. This leads to rapid decrease in plasma 18FFDG levels. Because of their high glucose-6-phosphatase levels, tissues (other than brain
18
F-FDG uptake. While 18F-FDG goes to almost all
GSPant\Newbook\15-chp\234
Radiopharmaceuticals in Clinical Nuclear Medicine
235
and heart) respond by releasing 18F-FDG, which is excreted in urine. The net effect is
selective trapping of 18F-FDG in brain and heart.
In metabolically active sites (most of the malignant lesions), where there is high demand
of glucose, 18F-FDG is picked up and trapped. Since it cannot undergo glycolysis, either it
remains trapped or goes back into the plasma for clearance. With insufficient quantity of
glucose-6-phosphatase it remains trapped in the lesion and can be imaged by positron emission
tomography.
Enzyme substrate
Radiopharmaceuticals, acting as substrates for specific enzyme-catalyzed reactions, can be
used to study those reactions. Here the substrate (with high specific activity) has to be
specific for the enzyme but without any physiologic or pharmacologic response. Use of
Radiolabeled fatty acids to study myocardial fatty acid metabolism is an example of this
mechanism. Similarly, Radiopharmaceuticals acting as substrate for microbial enzymes can
be developed and used to identify/diagnose a specific organism/infection.
Receptor binding
Receptors are protein molecules located on cell membrane or cytosol in very low
concentration, which initiate highly specific changes when activated by specific ligands or
their structural analogues. Changes in receptor concentration are known in many diseases
like diabetes mellitus, Parkinson’s disease, Schizophrenia, Huntington’s chorea etc. By
knowing the map of receptor density, diagnosis and response to treatment of many diseases
can be obtained.
There are some requirements for a radiopharmaceutical to be useful as a receptorimaging agent:
1. It should have high specific activity
2. It should have high binding affinity to the receptor
3. It should have low binding affinity to non-receptor binding sites
Potentially radiopharmaceuticals can be designed for the receptors of microbial agents.
If this can be realized, it can lead to a whole new class of radiopharmaceuticals capable of
identifying etiologic agents in many disease processes.
123
I-MIBG acting as a ligand for
adrenergic receptors, 6-18F-fluoro-dopa for dopamine receptor, 11C-carfentanil for opioid
receptor, 11C-flumanezil and
11
C-PK11195 for benzodiazepine receptors,
11
C-labeled
imipramine for norepinephrine receptor and 11C-N-methyl-3-piperidinyl benzilate for
cholinergic receptor are some of the examples of this mechanism.
Antigen-antibody reaction
Radiolabelled monoclonal antibodies with their immunologic specificity act against a specific
GSPant\Newbook\15-chp\235
236
Radiopharmaceuticals in Clinical Nuclear Medicine
target antigen.
111
In Oncoscint (Anti-CEA antibody) is useful in the detection of recurrence
of colorectal cancers. In the presence of rising CEA levels after surgery with normal CT/MR
studies, it is useful in identifying the source of rising CEA. Antigenic diversity of the
tumors, inadequate dose delivered to the target region are some of the limiting factors in the
widespread use of monoclonal antibodies.
Quality Control
Radiopharmaceuticals are administered to the patients either for diagnostic investigations or
for therapeutic purposes. It is therefore essential that they are sterile and free from pyrogens
and should pass through strict quality control tests before being administered to the patient.
Except in automated systems, at some stage in the preparation the ingredients come in
contact with the atmosphere with some risk of contamination. In addition to increased risk
of microbial contaminations, there is risk of radiation exposure particularly with prolonged
preparation time and spillage. The product needs to be protected from environment, operator
and others involved in the preparations. The operator also has to be protected from radiation
and pathogenic organisms. Further the entire facility should be protected from radioactive
and microbial contamination.
Physical Quality Control
The following physical parameters of a radiopharmaceutical have to be checked on their
procurement before use. They should be stored under optimum conditions of temperature
and humidity as per instruction by the manufacturer.
1. Physical appearance
2. Color
3. pH
4. Particle size
5. Turbidity
Change in any one of these parameters should be seriously viewed and product may be
rejected.
Chemical Quality Control
Chemical quality control is mainly divided into three parts:
1. Radiochemical purity
2. Chemical purity
3. Radionuclide purity
Radiochemical Purity
This is defined as the proportion of the radionuclide present in the stated chemical form.
GSPant\Newbook\15-chp\236
Radiopharmaceuticals in Clinical Nuclear Medicine
237
Radiochemical impurities arise from decomposition due to the action of solvent, change in
temperature or pH, light, presence of oxidizing or reducing agents, and radiolysis. Control
over radiochemical purity is important to ensure the correct biodistribution of the
radiopharmaceutical and prevent possible errors in diagnosis and the delivery of an
unnecessary radiation dose to other organs. Examples are free
99m
in
Tc labeled complexes and free
131
I in
131
I labeled preparations. In order to determine
99m
Tc and hydrolysed
99m
Tc
radiochemical purity it is necessary to separate and quantify the various radiochemical
species that may be present. A number of techniques are available for this purpose such as
chromatography, gel filtration and electrophoresis.
Chemical Purity
The chemical purity of a radiopharmaceutical is the fraction of the material in the desired
chemical form. Causes of chemical impurities include the breakthrough of substances from
a generator column during elution (e.g. aluminum ion in a
by reagents used in the production process. Chemical impurities are also formed due to
breakdown of the material either before or after labeling. However, additives, acid, alkali,
and buffers are not considered impurities if used as per specifications. Chemical impurities
can have adverse consequences such as toxic effects or interactions with radiopharmaceuticals.
For example, aluminum ion can interact with
that embolize in the lungs or with
99m
99m
Tc- sulfur colloid to form flocculent particles
Tc-labeled bone agents to form colloidal precipitate
that is phagocytosed by the liver. Consequently, limits have been established for chemical
purity and are detailed for specific radiopharmaceuticals. For example, the USP 26 limit is
10 g Al/ml
99m
Tc for fission-produced 99Mo. Another example of chemical impurity is
presence of globulins in albumin preparations. Chemical impurities can be detected with a
variety of chemical analysis techniques such as photospectrometry, evaluation with dyeimpregnated paper, and gas or liquid chromatography.
99m
Tc eluate) and contamination
Radionuclide Purity
Radionuclide purity may be defined as the proportion of the total activity present in the
form of the stated radionuclide, the proportion generally being expressed as a percentage.
Radionuclide impurities may be present as a result of:
(a) The manufacturing process, for example, the presence of
125
alternative nuclear reactions
(b) The presence of parent nuclide when the latter is obtained by a separation technique
such as generator elution, for example, 99Mo in
99m
Tc
(c) The presence of radioactive daughter products of the stated radionuclide, for example,
the presence of 47Sc in 47Ca.
All radioactive medicinal products should be assayed for radioactive content prior to
administration. This assay, however, does not always allow identification of the nuclides
GSPant\Newbook\15-chp\237
I in
123
I caused by
238
Radiopharmaceuticals in Clinical Nuclear Medicine
giving rise to that radioactivity. It is possible therefore, to have a product containing the
required level of activity, but which may contain significant amount of other unwanted
radionuclides. As a consequence, biological distribution may be altered leading to degraded
scintigraphic images and the radiation dose delivered will be different than estimated because
of the differing energy characteristics of the impurity. Problems are generally encountered if
the impurity has a longer half-life than that of the stated radionuclide. This is illustrated by
the presence of
202
Tl (half-life 12.2 d) in
use beyond three days after the reference date. Thallium-201 may also contain
201
Tl (half-life 73 h), which makes it unsuitable for
200
Tl (halflife 26.1 h) as an impurity. It is, therefore, necessary to allow sufficient time to elapse
between preparation of
201
Tl and its use, to permit the level of
200
Tl to decay to an acceptable
level.
If the impurities have different chemical properties, they can be separated by appropriate
chemical methods. Radionuclidic purity is determined by measuring the half-lives and
characteristic radiations emitted by individual radionuclides. Radionuclides that emit gamma
rays are distinguished from one another by identification of their energies with -ray
spectrometry. Pure emitters may be checked for purity with a spectrometer or a liquid
scintillation counter. Since a given radiation may belong to a number of radionuclides,
determination of radiation energy alone does not establish the identity of a radionuclide. Its
half-life also must be established, and this can be accomplished by measuring and plotting
the activity under the photopeak in question over a period of time.
The US pharmacopoea limit of 99Mo breakthrough is <0.15 Ci of 99Mo per mCi of
99m
Tc activity. The 99Mo breakthrough in the elute can be measured by covering the vial
with a 6 mm thick lead container which absorbs almost all the 140 KeV photons from
99m
Tc.
The lead shielded vial is then placed in dose calibrator for measurement. Only 780 KeV
photons from the decay of 99Mo are detected through the lead shield and the 99Mo
breakthrough is measured.
Biological Quality Control
The biological tests include:
(a) Sterility
(b) Pyrogenicity
(c) Biodistribution
Sterility
The purpose of sterility testing is to ensure that the procedures used in the radiopharmacy
result in sterile products, i.e. absence of any viable bacteria or microorganisms in a
radiopharmaceutical preparation. All preparations for human administration must be sterilized
by suitable methods that depend on the nature of the product. There are various ways of
getting microorganism free preparations.
GSPant\Newbook\15-chp\238
Radiopharmaceuticals in Clinical Nuclear Medicine
239
They are:
1. Sterilization by dry heat (180° C for 2 hrs) of items like column, beaker, tubes,
bottles etc.
2. Sterilization by wet heat (120oC for 45 minutes) of items like eluted
99m
Tc, rubber
corks, vials etc.
3. Gaseous sterilization plastic materials (Ethylene dioxide gas)
4. Millipore filtration (0.22 m filters) for various solutions in the laboratory such as
eluted
99m
Tc from generator
5. Ultraviolet light for laminar flow fume hood etc (Overnight)
6. Radiation sterilization for packed syringes and other disposables with gamma rays.
Pyrogenicity
Pyrogens are proteins or polysaccharide, typically bacterial endotoxin. They are 0.05-1 mm
in size, heat stable, filterable and soluble in water. Intravenous injection of pyrogen containing
solutions may produce fever, chills, leukopenia, pain in joints, flushing, headache and
sweating. It is, therefore, pertinent to have the pyrogen test before any radiopharmaceutical
is subjected for administration. For all radiopharmaceuticals, the endotoxin concentration
limit is 175/V USP EU per ml of injection per kg, where V is the maximum recommended
total dose in milli litre. The maximum permissible dosage for parenteral administration
(except intrathecal) is 5.0 EU/kg, whereas it is 0.2 EU/kg for intrathecal administration.
Pyrogenicity may be checked by rabbit test and/or Lal test.
Rabbit Test
As per USP the test solution/material is injected in a group of rabbit having rectal temperature
variation less than 0.6oC. In case, there is a rise by less than 1.4oC, the sample is assumed to
be free from pyrogen and fit for patient use.
Limulus Amebocyte Lysate Test (LAL)
This test is very much accepted for short lived radiopharmaceuticals. In this test 0.1 ml of
LAL and the test sample at pH 6-8 are mixed. The sample is observed for 15-60 minutes
after mixing for gel formation. The formation of gel indicates the presence of pyrogen.
This is very sensitive method.
Biodistribution
Biodistribution of any radiopharmaceutical is most essential quality control test to establish
its efficacy and in vivo usefulness. This includes tissue distribution, plasma clearance,
urinary and fecal excretion. Animal studies are done to establish biodistribution before they
can be used in humans. In biodistribution studies, the radiopharmaceutical is administered
to animals and they are sacrificed at different time intervals. The activities (radioactive
GSPant\Newbook\15-chp\239
240
Radiopharmaceuticals in Clinical Nuclear Medicine
counts) in different organs are counted and compared. Some animals may be subjected to
imaging procedure also. Biodistribution studies are also used for dosimetry of internal
emitters.
References
1. Early PJ and Sodee DB. Principles and Practice of Nuclear Medicine. Mosby publication (2
edition), 1995.
2. Karesh SM. “Principles of radiopharmacy,” in Nuclear Medicine, Eds: Henkin RE, Boles MA, Dillehay
GL, Halama JR, Karesh SM, WagnerRH, Zimmer AM. Mosby-Year Book, Inc. St. Louis. 1996; pp.
334-349.
3. Ercan MT, Caglar M. Therapeutic radiopharmaceuticals. Curr Pharm Des 2000 Jul; 6(11): 1085-121.
4. Britton et al. Imaging bacterial infection with (99m)Tc-ciprofloxacin (Infecton). J Clin Pathol 2002
Nov; 55(11):817-23.
nd
GSPant\Newbook\15-chp\240
Nuclear Medicine in Diagnosis and
Therapy — an overview
Chetan Patel, Madhavi Chawla and C S Bal
Nuclear medicine is a branch of medicine and medical imaging that uses the properties
of radioactive material in diagnosis and therapy. Diagnostic nuclear medicine procedures
involve the use of radiopharmaceuticals which are administered to patients and the radiation
emitted is measured by external detectors. The majority of the diagnostic tests are carried
out with gamma camera imaging. Other diagnostic tests use probes to acquire measurements
from parts of the body, or counters for the measurement of samples taken from the patient.
The functional and morphological data provided by nuclear medicine evaluation contributes
to improved diagnosis. Nuclear medicine imaging differs from other imaging modalities in
that the tests primarily show the function of the system being investigated as opposed to the
anatomy. This helps the physician in diagnosis and understanding the disease process for
proper management. Tumors, infection and other disorders can be detected by evaluating
organ function. Radionuclides are also used for the treatment of some malignant and benign
conditions. They also provide pain palliation in some disease conditions.
Historic Development of Nuclear Medicine
The pace of growth of nuclear medicine as a subspecialty of medicine reflects the impetus
provided by the clinical investigator, the physiologist, the radiopharmacist, the physicist and the
instrument designer. A major development in gamma ray detection occurred in 1947-48 when
Coltman and Marshall (1) in United States used photomultiphier tubes to detect individual
scintillations. Cassen et al (2,3) at the University of California (U.C.L.A) used calcium tungstate
detector to make a sensitive directional gamma ray rectilinear scanner. Nuclear medicine has
since then grown into a full fledged and well-established discipline, the impact of which is felt in
most branches of medicine. The rectilinear scanner could not remain popular due to its slow
mechanical movement and thus an unusually long time for imaging large organs. In 1957 Anger
(4,5) described a scintillation detector using parallel hole collimator and sodium iodide (thallium
24 1
Соседние файлы в папке Библиотека им академика М.И. Перельмана