Pathway discovery leads to liver drug treatment?
caused by liver disease may lead to a drug treatment that would
restore learning ability and provide a viable alternative to
Sildenafil, commonly known as Viagra.
It is hoped the study may be able to determine why liver disease sometimes causes hepatic encephalopathy, which causes intellectual impairment due to hyperammonemia (high levels of ammonia in the blood).
The hope is that in determining the pathway, a pharmacological treatment can be devised which may prove useful for the clinical treatment of patients with overt or minimal hepatic encephalopathy.
Hyperammonemia is considered one of the main factors responsible for brain alterations in hepatic encephalopathy. Clinical treatments are directed toward reducing blood ammonia levels. However, the mechanisms of action by which hyperammonemia and liver failure lead to neurological alterations and a decrease in intellectual function remain unclear.
The latest research published in the February 2005 issue of Hepatology, hypothesised that impaired learning was due to a defect in the glutamate-nitric oxide-cGMP pathway in the brain and that administering sildenafil to increase cGMP would restore learning ability. Sildenafil, commonly known as Viagra, is known to prevent the destruction of cGMP and allow it to accumulate in the body.
Researchers examined four groups of rats: rats in which they constructed portacaval shunts (a treatment used to treat high blood pressure); rats with portacaval shunts that were given sildenafil; rats that were fed an ammonium-containing diet; and rats that were fed the diet and given sildenafil.
Results showed that while rats with the portacaval shunt showed a reduced learning ability, treatment of shunted rats with sildenafil restored their ability to learn. cGMP concentrations were reduced in the brain extracellular fluid of shunted rats compared with controls. Treatment with sildenafil restored levels of cGMP in the rats.
Further tests showed a 74 per cent reduction in the function of the glutamate-nitric oxide-cGMP pathway in shunted rats, while treatment with sildenafil significantly enhanced the function of this pathway.
"The results indicate that hyperammonemia, is responsible for the alteration of the function of the pathway and, subsequently, of the impairment of learning ability," the authors stated.
They note, however, that an excessive increase in cGMP may impair learning and that it must be kept high but below a certain threshold to reach maximum learning ability.
"Although caution must be taken considering the possible deleterious increase in the existing vasodilatation in liver disease by sildenafil, pharmacological manipulation of cGMP in brain by safe procedures may be a useful treatment to restore cognitive and intellectual functions in patients with overt or minimal hepatic encephalopathy," the authors concluded.
According to the World Health Organization (WHO), chronic liver disease (CLD) causes up to 1.4 million deaths worldwide annually. With a predicted boom in numbers of those with CLD, Datamonitor believes that the market for antifibrotic therapy represents untapped potential.
There is currently no single antifibrotic treatment option. However, a wide range of likely molecular targets for antifibrotic therapy have been identified, for example those directly involved in fibrogenesis, including matrix metalloproteinases and their inhibitors, and broad-range pro-fibrogenic cytokines, such as tumor necrosis factor alfa (TNF-alfa) and tumor growth factor beta (TGF-beta).
Datamonitor has identified liver fibrosis/cirrhosis as a disease area with high blockbuster ($1 billion (€770 million) in sales) potential. Key reasons for this prediction include the high prevalence of liver fibrosis and cirrhosis in the developed world, the potentially long duration of antifibrotic therapy, and the possibility of several points of intervention for antifibrotic therapy, such as fibrosis and cirrhosis.
