A pilot study to investigate the use of oxpentifylline (pentoxifylline) and thalidomide in portal hypertension secondary to alcoholic cirrhosis.
BACKGROUND
Tumour necrosis factor-alpha is thought to be important in the pathogenesis of portal hypertension. Oxpentifylline (pentoxifylline) and thalidomide inhibit endotoxin-induced tumour necrosis factor-alpha production in vitro.


OBJECTIVE
To assess the toxicity of oxpentifylline (pentoxifylline) and thalidomide in cirrhosis and their effect on the hepatic venous pressure gradient and tumour necrosis factor-alpha production.


METHODS
In an open-label pilot study, 20 abstinent patients with stable alcoholic cirrhosis and oesophageal varices were recruited; 12 patients completed haemodynamic measurements before and after treatment with oxpentifylline (pentoxifylline) 1800 mg (n=6) or thalidomide 200 mg (n=6) daily for 2 weeks. Tumour necrosis factor-alpha production was assessed in ex vivo monocyte cultures stimulated with endotoxin.


RESULTS
Thalidomide reduced the hepatic venous pressure gradient from 19.7 mmHg (9.3-23.5 mmHg) to 12.2 mmHg (4.7-19.5 mmHg) (P=0.03) without reducing the hepatic blood flow or altering systemic haemodynamic parameters. Thalidomide reduced ex vivo tumour necrosis factor-alpha production by approximately 50%. Oxpentifylline (pentoxifylline) had no significant effect on any of the parameters measured. Side-effects led to dose reduction or treatment withdrawal in 40% of patients.


CONCLUSIONS
Thalidomide, but not oxpentifylline (pentoxifylline), reduces the hepatic venous pressure gradient in stable alcoholic cirrhotics, an effect that may be mediated by the inhibition of tumour necrosis factor-alpha production. The role of tumour necrosis factor-alpha inhibitory drugs in the therapy of portal hypertension should be investigated in a randomized controlled trial.
Austin
A S
AS
Division of Gastroenterology, University Hospital, Queens Medical Centre, Nottingham, UK.
Mahida
Y R
YR
Clarke
D
D
Ryder
S D
SD
Freeman
J G
JG
D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008104:Liver Cirrhosis, Alcoholic / Q000150:complications* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010431:Pentoxifylline / Q000009:adverse effects / Q000627:therapeutic use*; D010865:Pilot Projects; D013792:Thalidomide / Q000009:adverse effects / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014665:Vasodilator Agents / Q000009:adverse effects / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D013792:Thalidomide; D010431:Pentoxifylline