Low trough levels of tipranavir in a combination antiretroviral therapy of tipranavir/ritonavir and tenofovir require therapeutic drug monitoring.

The new non-peptidic protease inhibitor tipranavir is used boosted with ritonavir in a 500/200 mg bid scheme. Multiple drug interactions are described for both drugs because of their different action in CYP450 3A4 and p-glycoprotein. In this retrospective analysis of 22 patients during therapy with tipranavir/ritonavir (TPV) 500 mg/200 mg bid, we found significantly decreased TPV-trough levels in combination with tenofovir (15.32+/-5.22 microg/ml) in comparison to TPV trough levels without tenofovir (20.21+/-14.87 microg/ml). Therapeutic drug monitoring of TPV is recommended.

Safety of long-term lopinavir plasma-levels in patients with liver disease.

Chronic liver disease is often found in HIV infected patients. LPV as first choice drug is often used over long time periods. TDM as a tool in patients care is important but the knowledge of LPV-plasma-levels in patients with chronic liver disease remain uncertain. With this retrosepective analysis we want to show if there are differences in LPV-plasma-levels between patients with and without chronic liver diseases over a long-time period. LPV-plasma-levels were analysed with an HPLC-based methode. The LPV-plasma-levels over the time course in patients with chronic liver disease (n = 30) and patients without liver disease (n = 38) was evaluated. Liver function tests, CD4-cell count and HI-viral load was also correlated with liver disease. The LPV plasma-levels of n = 450 samples from 30 patients with liver disease (Hepatitis B: n = 17, Hepatitis C: n = 16, Alcoholic liver disease: n = 7) were determined over 18.7 +/- 16,3 months (1 - 48.5 months). A median of 10 samples per patient was eligible (2 - 50 samples). There are no significant differences according to liver disease in LPV-plasma levels (mean Ctrough without: 5917 +/- 4811 ng/ml, mean Ctrough with liver-disease: 6564 +/- 4517 ng/ml, p > 0.05). The intraindividual and interindividual variation of LPV-plasma levels, CD-4 increase, HI-virus suppression and liver tests in patients with and without liver disease is comparable. In this clinical setting no differences in LPV-plasma levels between patients with and without chronic liver disease could be demonstrated. LPV-therapy in patients with chronic liver disease is therefore safe. In patients with impaired liver function TDM is a helpful tool for dose adjustment.

High performance liquid chromatographic method for the determination of HIV-1 protease inhibitor tipranavir in plasma of patients during highly active antiretroviral therapy.

A new high-performance liquid chromatographic method for the determination of tipranavir in human plasma is described. Quantitative recovery following liquid-liquid-extraction with diethylether from 100 microl of human plasma was achieved. Subsequently, the assay was performed with 67 mM potassium dihydrogen phosphate-acetonitrile as a mobile phase, a Phenomenex C 18 column and UV detection at 255 nm. Linear Standard curves were obtained for concentrations ranging from 2.5 to 400 microg/ml. The calculated intra- and inter-day coefficents of variation were below 7%.

Incidence and pathophysiology of peptic ulcer bleeding.

Peptic ulcer accounts for about 50% of all cases of upper gastrointestinal bleeding. Acute mortality may be as high as 14%. Infection with Helicobacter plyori (Hp) and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) are the predominant risk factors. While the prevalence of Hp in ulcer bleeding is still debated, there is strong evidence that eradication of bacteria reduce the risk of re-bleeding significantly. The use of NSAIDs increases the frequency of ulcer bleeding about four- to sixfold on average. Additional factors such as advanced age, concomitant use of corticosteroids or anticoagulants, prior ulcer complications and co-morbid diseases may further increase the risk of bleeding. Whether or not Hp infection also represents an additive risk factor in NSAID-related bleeding remains to be clarified. The pathophysiologic action of both Hp and NSAIDs is quite complex. Hp promotes the aggressive factor acid and damages several mucosal defence mechanisms by liberating lipopolysaccharide, urease and vacuolating cytotoxin. In NSAID toxicity the cyclo-oxygenase enzymes (COX) have been studied intensively. With the advent of COX-2-selective NSAIDs, the clinical problem of NSAID-induced ulcer bleeding may be markedly reduced or abolished completely.