A new study rats reveals the mechanism responsible for learning impairment due to liver failure and shows that sildenafil restores cognitive function -

Liver disease sometimes causes hepatic encephalopathy, which involves brain damage, personality changes, and intellectual impairment due to hyperammonemia (high levels of ammonia in the blood). However, the mechanisms involved in both learning and how liver disease leads to learning impairment are unclear.

In a new study led by Vicente Felipo of the Laboratory of Neurobiology at the Fundacion Valenciana de Investigaciones Biomedicas in Valencia, Spain and published in the February 2005 issue of Hepatology, researchers hypothesized 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. Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD), published by John Wiley & Sons, Inc. is available online via Wiley InterScience at interscience.wiley.com/journal/hepatology.

Researchers examined four groups of rats in their study: rats in which they constructed portacaval shunts (a treatment used to treat high blood pressure in the liver due to liver disease that is believed to be one of the causes of hepatic encephalopathy, and also a model of chronic liver failure in rats); 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. They also used control groups consisting of rats fed a normal diet both with and without sildenafil. All animals were subjected to a maze learning test four weeks following surgery or from the date when drug treatment began. Levels of both cGMP and ammonia in brain were measured using a microdialysis probe.

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. Tests showed that the concentration of cGMP was reduced in the extracellular fluid in brains of shunted rats compared with controls and that treatment with sildenafil restored levels of cGMP in these animals. In addition, further tests showed a reduction of 74 percent in the function of the glutamate-nitric oxide-cGMP pathway in shunted rats, while treatment with sildenafil significantly enhanced the function of this pathway. These evaluations were also performed on rats with hyperammonemia. Results showed that chronic hyperammonemia significantly reduced the rats' ability to learn, but that treatment with sildenafil restored their learning ability. While sildenafil treatment restored levels of cGMP and enhanced the function of the glutamate-nitric oxide-cGMP pathway in hyperammonemic rats, it did not affect ammonia levels.

"The fact that rats with portacaval anastomosis [shunts] or with hyperammonemia without liver failure show the same alterations in the function of the [glutamate-nitric oxide-cGMP] pathway, extracellular cGMP and learning ability indicates that hyperammonemia, which is the only common alteration in both models, is responsible for the alteration of the function of the pathway and, subsequently, of the impairment of learning ability," the authors state. 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.

The authors conclude: "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."
Article: "Oral Administration of Sildenafil Restores Learning Ability in Rats with Hyperammonemia and with Portacaval Shunts," Slaven Erceg, Pilar Monfort, Mariluz Hernández-Viadel, Regina Rodrigo, Carmina Montoliu, Vicente Felipo, Hepatology; February 2005; 41:2.

John Wiley & Sons, Inc
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Tuesday, 11 May, 1999, 17:28 GMT 18:28 UK Viagra 'limited to cut cost'
The government anticipated a huge demand for Viagra
The government put restrictions on the NHS prescription of Viagra because it feared a rush for the drug would create huge expense, a High Court judge was told on Tuesday.

The fears were described during a legal challenge to the Government's original decision to issue advice limiting the NHS availability of the anti-impotence drug.

Mr Justice Collins reserved judgment following a two-day hearing.

Pfizer Ltd, manufacturers of the drug, attacked a health service circular issued last September advising doctors not to prescribe Viagra, unless in exceptional circumstances.

David Pannick QC, for the company, said Health Secretary Frank Dobson had acted outside his powers by effectively using the circular to impose a ban.

He had also acted in breach of EU law as he attempted to prevent the best-selling love drug becoming a "serious drain" on NHS funds, said the QC.

Presiley Baxendale QC, appearing for the Health Secretary, said worldwide publicity about the Viagra had led to fears that doctors would come under huge pressure to prescribe the drug, particularly as it has been suggested it could enhance sexual performance.

Ms Baxendale said: "I accept the Secretary of State was very concerned about resources."

It was feared that, if action was not taken, Viagra could have cost the NHS between £60m and £125m a year.

Ms Baxendale said she accepted the aim of the circular was to "deter the rush", but there was a difference between a ban and something which was interim advice and guidance while consultations took place before a final policy was decided upon.

The advice did not stop GPs exercising their judgment, but at the same time they were perfectly entitled to take it into account.

Unlawful interference

Mr Pannick said he accepted that the circular was not a ban, as such, but its effect was to act as a ban - "and that was what was intended".

This unlawfully interfered with a doctor's "statutory right and legal duty to prescribe according to their assessment of clinical need."

If the Health Secretary wanted to impose restrictions, the correct course was to obtain Parliamentary approval and place the drug on the relevant medical schedule.

Mr Dobson had now shown an "impeccable sense of timing" by announcing last Friday that he proposed to take that course of action, said Mr Pannick

Since the September guidance was issued, the government has published its views on which patients should receive Viagra.

Last week, it increased the number of men who could get the drug.

They include men with diabetes, prostate cancer and Parkinson's Disease.

Impotence experts say the list is still restrictive and discriminatory.

Reserving judgment, the judge said he hoped to give his decision on the challenge within a month.

Internet links:

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Oral Medications in the Management of Erectile Dysfunction

from Journal of the American Board of Family Practice

Safety and Tolerability

When choosing an agent to treat erectile dysfunction, important issues to consider include safety, tolerability, and convenience. Because these medications are used to improve the patient's quality of life, agents that have marked adverse effects, are invasive, or are inconvenient might not be first options. In addition to being noninvasive and convenient, all three oral medications for erectile dysfunction appear to be well tolerated and have minimal and transient side effects at their recommended dosages. Priapism, a concern with the penile injection therapies and urethral suppositories, does not appear to be an issue with the oral medications; therefore, adverse effects might not be a major factor when choosing among these agents.

Many clinical trials evaluating yohimbine did not include information on adverse effects. When examining those trials that did include this information, the most common adverse effects observed with yohimbine included anxiety, increased urinary frequency, tachycardia, and increased arterial pressure.[3,4] In a study by Teloken et al[5] in which patients received 100 mg of yohimbine daily, a dose three to five times higher than used in other trials, 32 percent of patients experienced an increase in urinary frequency compared with 14 percent taking placebo. A fairly high percentage of patients taking yohimbine reported tachycardia (27 percent), whereas none of the patients on placebo experienced an increased heart rate. Only one study of yohimbine included in this review reported patient dropout rates resulting from adverse effects. This study included 82 patients in a crossover design, and 8 patients (10 percent) discontinued therapy because of adverse effects of treatment with yohimbine.[4] The adverse effects were similar to those previously mentioned. In a trial by Rowland et al,[6] the more common adverse effects in the yohimbine group included disturbed sleep, mild diarrhea, lack of energy, and, surprisingly, lower sexual desire.

Sildenafil and phentolamine are generally well tolerated by most patients according to the available clinical trials. Goldstein et al[7] conducted two trials of sildenafil with a total of 861 patients. Adverse effects included headache (12 to 30 percent), flushing (10 to 27 percent), and dyspepsia (3 to 16 percent) with rates being dose dependent. Additionally, dose-dependent transient visual disturbances, or changes in the perception of color hue or brightness, were reported by 2 to 9 percent of men. The manufacturer reports a rate of 3 percent for transient color vision changes. Between 6 and 15 percent of patients withdrew from the trials during treatment with sildenafil compared with 8 to 17 percent of those receiving placebo. Discontinuation because of treatment-related adverse effects was 1 to 2 percent. Additional reasons for discontinuation included insufficient response, protocol violations, and withdrawal of consent, among others.

Recently there have been several reports of deaths occurring with concurrent sildenafil and nitrate use. These drugs in combination cause potentially fatal decreases in blood pressure. According to the manufacturer, sodium nitroprusside use is also contraindicated, but other nonnitrate vasodilators (b-blockers, a-blockers, angiotensin-converting enzyme inhibitors, diuretics, and calcium channel blockers) have not been shown to be a problem. Sildenafil should never be administered to a patient concurrently taking nitrates or sodium nitroprusside or to a patient who might inadvertently receive a nitrate after exertion or sexual activity.

Nasal congestion was reported as the only adverse effect, with one patient experiencing it, in the smallest study of phentolamine.[8] In two trials reported by Zorgniotti,[9] 6 percent of patients complained of nasal congestion and 2.3 percent complained of faintness or dizziness, relieved by lying down. Another study excluded patients with intolerance to phentolamine (increased blood pressure and pulse) before randomization by giving a test dose; therefore, no adverse effects were mentioned in the results.[10] This methodology could limit the generalizability of these results to general practice. Information available from the manufacturer of phentolamine lists insomnia, nasal congestion, and dyspepsia as common adverse effects.

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Effect on Lipodystrophy

Based on preliminary data at week 48 from a substudy of the AI424-034 trial, it would appear that atazanavir has little effect on changes in fat redistribution.[35] In this substudy, dual x-ray absorptiometery (DXA) and cross-sectional computed tomography (CT) were performed at baseline and at week 48. At week 48, DXA scans revealed small, comparable increases in appendicular fat (3% vs 3%), truncal fat (5% vs 8%), and total body fat (5% vs 5%) for atazanavir versus efavirenz. Cross-sectional CT scans showed no change from baseline in the ratio of visceral adipose tissue:total adipose tissue for both regimens. Another trial (AI424-007/AI424-041) comparing unboosted atazanavir with nelfinavir revealed that 13% and 8% developed investigator-reported lipodsytrophy, 0% and 1% developed a buffalo hump, and 5% and 2% developed gynecomastia, respectively.[35] A recent case series of three patients reported a regression of dorsocervical and abdominal fat accumulation after switching the existing protease inhibitor in their HAART regimen for atazanavir.[62] However, careful long-term studies will be needed to assess the true effect of atazanavir on lipodystrophy.

Previous PageSection 7 of 12Pharmacotherapy 24(12):1732-1747, 2004. © 2004 Pharmacotherapy Publications
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