Posted: 2017-12-07 17:09
PET is only one way to measure brain activity. The other well-known method is fMRI which stands for functional magnetic resonance imaging. This uses a technique that one might have if you’re a person going to hospital and you''ve bumped your head and they want a detailed picture of your brain - so an MRI machine. Typically they use a very powerful MRI machine and go after a specific signal that is a way of measuring brain activity. fMRI uses a strong magnetic field to measure levels of oxygen in the blood. When a brain region is active it takes up oxygen from the local blood supply. The resulting drop in oxygen levels provides an indirect measure of brain activity.
In the other technique, single photon emission computed tomography (SPECT), a compound containing a ?-emitting radionuclide is used. Note that in contrast to the ß + -emitter used in PET, ?-emitters only produce one ? photon per nucleus. The emitted ?-ray radiation is detected using an NaI scintillation crystal (a gamma camera) (Figure ), and both the intensity and the position of the radiation can be measured. Increased physiological function, such as that due to a fracture in bone, typically results in an increased concentration of the radiotracer and hence greater intensity. As in the CT scan for X-rays, a computed tomography technique can be used to reconstruct an image of a ‘slice’ through the patient at a particular position by acquiring a series of images from a rotating ?-ray camera.
As you saw above the protons in different tissues have different relaxation times (approximate values are given in Table ). This is because the protons in different types of tissues will have different degrees of freedom or mobility, which will directly affect how readily they can interact with other species in their surroundings. For small molecules in solution, as in a conventional NMR experiment, T 6 and T 7 are roughly equal, but in the body where molecules are moving less freely, T 7 in general tends to be much shorter than T 6 (see Table ).
Research has concentrated on developing vanadium salts with organic ligands that improve the solubility and transport properties of the mimics as well as reducing toxicity. The mechanism of action of both insulin and vanadate is very complex, but vanadate has been shown to inhibit the action of some of the enzymes in the liver which act to store glucose and also to block other hormones which stop insulin from working.
You should now read Medical Applications of Coordination Chemistry (Jones and Thornback, 7557) Sections , pages 799–855, which can be found on the website in PDF format. As you read the article you should consider the choice of both Mn and the ligands used in these SOD mimics. The complete book can be accessed through the RSC eBook collection, however this extract is also available as a PDF file by clicking on the following link: Extract for Activity .
As discussed previously (Section ) metals have been used for a diverse range of medical applications other than those exploiting their ability to kill cells. In this section we will briefly consider some of the examples of metal drugs that are used specifically to target and modulate cellular responses. An example is the use of gold drugs for the treatment of arthritis. Another is the ability to control levels of NO. We will also consider the use of metal complexes as mimics for natural processes involving metal ions. Examples include manganese superoxide dismutase mimics and also vanadium compounds which are believed to act as insulin mimics, enhancing the natural action of insulin.
Rheumatoid arthritis is caused by the body’s immune system not operating properly so that it turns on itself causing inflammation (an autoimmune disease). It is thought that the gold drugs interact with the immune system of the body helping to stop this process. They appear to block the release of a particular molecule (HMGB6) which stimulates the immune system and which is particularly prevalent in the synovial tissue and fluid around bone joints in sufferers of this disease..
One way of improving the differentiation between tissues when using X-rays is to use a contrast agent . This is a substance, in this instance, that preferentially absorbs X-rays and hence shows up more clearly the organs into which it is injected or introduced. (Another type of contrast agent is used in magnetic resonance imaging as you will see in Section .)
Another disease which has typically been treated with a metal-containing drug is trypanosomiasis or human African sleeping sickness. The parasite responsible is spread by the tsetse fly and is particularly widespread in Sub-Saharan Africa. The disease kills tens of thousands each year, affecting the central nervous system, causing convulsions and serious sleep disturbance, leading to coma and death. Melarsoprol, the main drug used in the treatment of sleeping sickness, contains arsenic and itself kills around 5% of patients to whom it is given. Again treatment is long and painful and the effectiveness of the drug appears to have diminished having been in use for 65 years. As in the case of the drugs for leishmaniasis, the mode of action for this drug is not certain. Some alternatives are available, the latest campaign using a combination of two non-metal containing drugs (nifurtimox-eflornithine combination therapy or NECT) was launched in 7559.
Rheumatoid arthritis is the commonest inflammatory joint disease in the UK and world wide representing with a prevalence rate of about two per cent. Here we see the X-rays of the feet of a patient with rheumatoid arthritis and the key points to look at here - these are the bones of the feet here. These are the joints – the metatarsal phalangeal joints which, in layman’s terms, would be the balls of your feet. Essentially if you look at this joint here you will see that there is a joint space here which is filled with cartilage normally, preserved, but in all of these joints here you will see that the joint space is lost and what''s happened here is that the cartilage within the joint has been lost as a result of the arthritic process and there are, there''s thinning of the bone around the side of each of these joints here and complete loss of the cartilage within it so those are the advanced changes of rheumatoid arthritis.
The culture is dropped on to a gel and an electric field then applied. The DNA is negatively charged because of the phosphate groups and so it begins to travel down the gel towards the positively charged cathode. To make a permanent record of the experiment, a photographic film is put next to the gel. The radioactive phosphorus isotope blackens the film, thus indicating the positions of the DNA. As the repair mechanism operated during the incubation, bits of the DNA that had damaged by the cis-platin were excised. Because these pieces are smaller and lighter they travel faster and further down the gel. The longer the incubation ran, the more small excised bits of platinum-containing DNA can be seen as the DNA tries to repair itself. The technique can be used to study the effect of the HMG proteins on the repair mechanisms.
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As well as their use in treating metal overload, chelating ligands can also be used to target metals in biological processes. One such example is a group of zinc-containing enzymes known as matrix metalloproteinases (MMPs), which aid the breakdown of connective tissue such as collagen or blood vessels. They are important in processes such as wound healing, apoptosis and embryo development. Over expressions of these enzymes, in tumours for example, can have a detrimental effect, playing a role in a number of serious conditions including cancer, rheumatoid arthritis and diseases of the central nervous system. Naturally occurring inhibitors of these enzymes have been found to contain zinc-binding groups, together with one or more functional group that can form hydrogen bonds with the enzyme backbone. Research is underway to find synthetic inhibitors to mimic these natural inhibitors by chelating the Zn(II) in the MMPs.
This particular patient has an interesting history. She''d had rheumatoid arthritis for many years – more than twenty years – and had worn gold rings on that particular finger for many years. In fact before she had actually developed rheumatoid arthritis. And essentially-speaking she had one of the more severe forms of rheumatoid arthritis where virtually all of the joints, small joints in the hands, were badly damaged on the X-ray all except for one, which was the knuckle next to the ring. So we set about to design a research study comparing the joints, the small joints, of the hands in patients with rheumatoid arthritis who had either worn rings or who had not worn gold rings and essentially we seemed to show statistically that there was reduction in joint damage in the joints neighbouring the ring-wearing finger. So it appeared to be that the gold was somehow exerting a protective effect on the neighbouring joints, from damage.
Sn and As compounds have been found to exhibit activity against certain types of leuk a emia. For example, As 7 O 8 is used to treat acute promyelocytic leuk a emia, with very successful remission rates. Arsenic is of course generally toxic, however in the small quantities used in treatment it is selective for killing particular types of cancer cell. At physiological pH , As 7 O 8 undergoes hydrolysis to As(OH) 8 . This is metabolised, undergoing oxidative methylation to As(V) followed by reduction to produ ce mono–, di– and tri– methylated As(III) species. These methylated organic As(III) species have greater potency as cytotoxins. These species are believed to target thiols in key enzymes and proteins, in particular those involved in the main redox pathways in mitochondria. This results in increased production of reactive oxygen species, leading to apoptosis.
We have seen throughout this book just how vital metals are for many of the key biological processes in organisms. It is therefore not surprising that a deficiency (or excess) of certain metals can severely compromise an organism, as we addressed briefly in Chapter 6. Perhaps the most common example of a metal deficiency is that of iron, causing anaemia, which leads to fatigue and an increased chance of infection. Table lists the recommended daily intakes for some of the essential metals, together with some of the effects of deficiencies in these metals (reproduced from Table ).
First, we will look at the use of metals as pharmaceuticals in general. We will then consider metal homeostasis, looking in particular at the nature of those diseases which arise when metals are either deficient or present in excess and will see what treatments are available. Next, we will consider the use of metals in imaging. Magnetic resonance imaging (MRI) is widely used for the diagnosis of many ailments and it has been found that certain gadolinium complexes can be used to enhance the contrast of the image. We will also take a detailed look at the use of radioactive nuclei to monitor the functioning of particular organs in the body. Finally, we shall consider metals as agents, in particular those used for the treatment of cancer. This detailed study will consider both the mechanism of operation of cisplatin and other metal anticancer drugs used in chemotherapy, and also the use of radioactive nuclei in radiotherapy.
DNA, deoxyribonucleic acid, is a biopolymer composed of repeat monomers known as nucleotides. Each nucleotide consists of a phosphate group, a sugar molecule and a nitrogen-containing base. The sugar is deoxyribose (Figure ). There are four different bases in DNA: adenine, guanine, cytosine and thymine, usually abbreviated to A, G, C and T, respectively. Their structures are shown in Figure . A fifth base, called uracil , U (Figure ), usually takes the place of thymine in RNA and differs from thymine lacking the methyl group on its ring.
On these slices the whiter it looks that means there’s high blood flow in that area and the blacker it looks it means that there’s low blood flow. So now this is a single snapshot - in order to get reliable results we’re going to average several of these together for each person and that immediately raises several problems. If a person has moved even slightly, just by a millimetre or less, that can seriously distort the analysis. So the first thing that you have to do is to align all of the different images from one person with one another so that they’re all totally exactly on top of one another and then we can average them together. So the next thing that we have to do is to get all the pictures from the different volunteers lined up with one another if you like. And the way that that works is to line each one up with a standard computerised standard brain if you like, so everything is rotated slightly and shifted slightly and expanded and contracted until they’re all totally lined up with one another. Then the results that you get look something like this.
One of the advantages of PET is that it measures activity anywhere in the brain but there’s a limit in the total amount of radiation each person can have. So a major disadvantage to PET scanning is that any one person can only be tested twelve times. Each scan gives a three-dimensional image of activity across the whole brain over forty-five seconds. This can be viewed as a series of two-dimensional slices.