Protease inhibitors adverse effects

Candidate protease inhibitor drugs must be relatively specific for the HIV-1 protease. Many other aspartic proteases exist in the human body and are essential to a variety of body functions, including digestion of food and processing of hormones. An ideal drug thus must strongly inhibit the HIV-1 protease, must be delivered effectively to the lymphocytes where the protease must be blocked, and should not adversely affect the activities of the essential human aspartic proteases. 

The development of antiretroviral therapy has been a major challenge since the discovery of the human inununodeficiency virus (HIV). Early successes with nucleoside and non-nucleoside reverse transcriptase (RT) inhibitors, as well as the development of protease inhibitors have facilitated, in recent years, a highly active antiretroviral therapy (HAART), where a combination of drugs is simultaneously administered. In spite of significant improvements in the morbidity and mortality of HIV-infected patients, the rapid appearance of resistant HIV-variants, as well as adverse effects and high cost of contemporary drugs necessitate the continuous development of independent classes of anti-HIV agents. ... 

Nelfinavir (Viracept) is probably the most commonly used protease inhibitor because of its low incidence of serious adverse effects. Its most common side effects are diarrhea and flatulence these may resolve with continued use. In addition to the drugs contraindicated for use with all protease inhibitors, amiodarone, rifampin, and quinidine are contraindicated in patients taking nelfinavir. 

It is inhibitor of HIV-1 and 2 proteases. The common adverse effects include GIT disturbances, hypertriglyceridemia and elevation of serum aminotransferase. 

Blrk and Applebaum (41) have studied the adverse effects of soybean trypsin inhibitors on development and protease activity in Tribolium castaneum. In Sitophilus oryzae, high doses of soybean trypsin inhibitor caused adult mortality (42). The wound-induced accumulation of these inhibitors is discussed by C. A. Ryan elsewhere in this symposium. 

Several pathophysiological mechanisms have been proposed, including adverse effects of protease inhibitors on hepatocyte and fat cell function (143), mitochondrial toxicity from nucleoside analogues (144), excess of reactive oxygen species (145), and cytokine-mediated events... 

Lipid abnormalities are a major adverse effect of HIV protease inhibitors (160). In a 48-week comparison with nelfinavir, atazanavir did not significantly increase total cholesterol, fasting LDL cholesterol or triglyceride concentrations (+6.8%, -7.1%, +1.5% respectively), while the respective concentrations rose by 28%, 31%, and 42% in those who took nelfinavir. The incidence of grade 1—4 lipodystrophy was infrequent in both groups, but this endpoint was poorly defined in this study. 

Two case reports have suggested that when a protease inhibitor is used with a glucocorticoid the tendency to adverse corticosteroid effects is potentiated (969,970). Two HIV-positive patients developed severely disfiguring skin striae within 3 months of starting indinavir therapy (971). 

The most frequent adverse effects associated with nelfinavir are diarrhea and flatulence. Diarrhea can be dose-limiting but often responds to antidiarrheal medications. Like the other protease inhibitors, nelfinavir is an inhibitor of the CYP3A system, and multiple drug interactions may occur as described above. Interactions with antiretroviral agents are summarized in Table 49-4 others may be found in Table 4-2. 

Although sesame seed is not known to contain any protease inhibitors or other ANFs, high levels of oxalic and phytic acids may have adverse effects on palatability (Ravindran and Blair, 1992) and on availability of minerals and protein (Aheme and Kennelly, 1985). Decortication of seeds almost completely removes oxalates, but it has little effect on phytate (Ravindran and Blair, 1992). Complete decortication is difficult because of the small size of the seeds. 

In common with many other legume seeds, raw lentils contain some undesirable constituents, although the levels of these are not likely to be of concern in poultry feeding. Weder (1981) reported the presence of several protease inhibitors in lentils. Marquardt and Bell (1988) also identified lectins (hemagglutinins), phytic acid, saponins and tannins as potential problems but could find no evidence that these had adversely affected performance of pigs fed lentils. It is known that cooking improves the nutritive value of lentils for humans but the effects of consumption of raw lentils by non-ruminants have not been well documented (Castell, 1990). 

Indinavir sulfate is a protease inhibitor and is used in combinations for the treatment of viral infection. During the high risk of HIV infection, indinavir is combined with zidovudine and lamivudine.65 Indinavir sulfate should be used with caution in patients with hepatic impairment and avoided in patients with severe liver damage. Caution is needed in diabetic patients and in patients with hemophilia. Adverse effects of indinavir sulfate include nausea, vomiting, diarrhea, fatigue, dizziness, headache, skin rashes, and allergic reactions (hematuria). 

Common adverse effects of protease inhibitors As experience with the protease inhibitors has grown, two important adverse reactions that are common to all of them have been uncovered. 

Omeprazole, like cimetidine, can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). Other drugs, including antibiotics (erythromycin, chloramphenicol, isoniazid), antifungal drugs (ketoconazole, itraconazole, and analogues), some SSRIs (fluoxetine, paroxetine), other antidepressants (nefazodone), protease inhibitors (saquinavir), opioids (fentanyl), calcium channel blockers (diltiazem, verapamil), and disulfiram also compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22,39) (SEDA-22,41). 

VASODILATOR ANTIHYPERTENSIVES PROTEASE INHIBITORS t adverse effects of bosentan by ritonavir Inhibition of CYP3A4-mediated metabolism of bosentan Co-administration is not recommended... 

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