Biomedical Engineering Reference
In-Depth Information
FIGURE 10.16 Bismuth antiulcer complex. Suggested structure of a binuclear bismuth(III) complex with
citrate. The Bi atoms are orange while oxygen is red and carbon black. The complex may form larger clusters
with bridging citrate anions.
restricted to gastrointestinal therapy. Since the 1970s, two Bi(III) compounds have been most
commonly used worldwide; bismuth subsalicylate (BSS) for the prevention and treatment of diarrhea
and dyspepsia, and colloidal bismuth subcitrate (CBS; Figure 10.16) for the treatment of peptic
ulcers. Most ulcers are associated with the bacterium, Helicobacter pylori . In the 1990s, a new
Bi(III)-containing drug was developed, ranitidine bismuth citrate (RBC), which combines the
antisecretory action of ranitidine with the bactericidal properties of bismuth. Although the use
of bismuth containing drugs for years was declining, they are now again becoming increasingly
popular as combination pharmaceuticals due to developed antibiotics resistance by H. pylori .
All bismuth(III) drugs are chelates of complicated polymeric nature. In BSS, salicylate ligands
coordinate to bismuth atoms via chelation, with extraordinary variations in binding modes. In CBS,
Bi(III) is aggregated through citrate bridges and H-bonds to form complex polymers. The actual
structure determination of bismuth-based drugs is complicated by the ability of the drugs to change
composition with pH and concentration.
The exact reaction mechanism of Bi(III) drugs is not fully understood, but the therapeutic
activity may result from mucosa-protective properties and from degradation of H. pylori . There
is no doubt that Bi(III) possesses antimicrobial activity itself and not only its organic ligand as
was once believed. The major target for Bi(III) appears to be proteins and enzymes. Pathogenic
microorganisms such as H. pylori produce large amounts of enzymes, and Bi(III) inhibits several
of these enzymes, including alcohol dehydrogenase (ADH) and urease. The inhibition of ADH is
likely due to the displacement of Zn(II) by Bi(III) at the active site since Bi(III) has higher afi nity
for thiolate groups than Zn(II). Urease has long been regarded as a potential target for bismuth-based
drugs, as the enzyme catalyzes the degradation of urea into carbon dioxide and ammonia, which
helps to neutralize the acidic environment in order for the bacteria to survive the hostile environment.
Presumably, Bi(III) binds to exposed thiolates of the enzyme and blocks the entrance to the active
cavity of the enzyme.
10.7 CONCLUDINGREMARKS
As this chapter has demonstrated, inorganic chemistry plays an important role in biology and an
increasingly important role in modern drug development. In many cases, metabolism of essential
metal ions may be controlled by means of organic pharmaceuticals since an intimate synergism
exists between the function of inorganic elements and organic compounds of the body. Metal ions
control some of the fundamental biochemical processes such as DNA and RNA replication, and
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