ritonavir and Pancreatitis

Interleukin-18 (IL-18) is one of the mediators of both pancreas damage and systemic complications like hypotension and multi-organ dysfunction during acute pancreatitis. IL-18 is generated intracellularly from pro-IL-18 by caspase-1 mediated proteolysis. Active caspase-1 itself is generated intracellularly by the action of the inflammasome, autocatalysis and other stimuli. The anti-retroviral drug ritonavir inhibits conversion of inactive pro-caspase-1 to active caspase-1. Since ritonavir is well tolerated in short-term use it may therefore prove useful in treating acute pancreatitis by lowering caspase-1 mediated IL-18 formation and the many inflammatory mediators downstream from that. The alcoholism treatment drug disulfiram has been in continuous use since the 1950s. It likewise has a low risk profile. Disulfiram inhibits several human proteases, among them caspase-1. Given the current morbidity and mortality of pancreatitis, research should be directed to ritonavir and disulfiram as treatment options for illnesses like pancreatitis where excessive IL-18 contributes to pathology. The first clinically used angiotensin converting enzyme inhibitor, captopril, has shown potent caspase-1 inhibiting activity as well and should be investigated in rodent models of human pancreatitis.

Topics: Acute Disease; Animals; Antihypertensive Agents; Captopril; Caspase Inhibitors; Disulfiram; Drug Synergism; Enzyme Inhibitors; Humans; Interleukin-18; Models, Biological; Pancreatitis; Remission Induction; Ritonavir; Time Factors

HIV protease inhibitors are an integral part of effective anti-HIV therapy. The drugs block HIV protease, prevent proper packaging of HIV virions, and decrease the HIV viral burden in the peripheral blood of infected individuals. In addition to direct anti-viral effects, the HIV protease inhibitors also modulate apoptosis. A growing body of work demonstrates the anti-apoptotic effects of HIV protease inhibitors on CD4+ and CD8+ T cells during HIV infection. The mechanism of this apoptosis inhibition is supported by several proposed hypotheses for how they alter the fate of the cell, including preventing adenine nucleotide translocator pore function, which consequently prevents loss of mitochondrial transmembrane potential. More recently, the anti-apoptotic effects of the HIV protease inhibitors have been tested in non-HIV, non-immune cell, whereby protease inhibitors prevent apoptosis, and disease in animal models of sepsis, hepatitis, pancreatitis and stroke. Interestingly, when HIV protease inhibitors are used at supra-therapeutic concentrations, they exert pro-apoptotic effects. This has been demonstrated in a number of tumor models. Although it is unclear how HIV protease inhibitors can induce apoptosis at increased concentrations, future research will define the targets of the immunomodulation and reveal the full clinical potential of this intriguing class of drugs.

Topics: Animals; Apoptosis; Hippocampus; HIV Infections; HIV Protease Inhibitors; Humans; Mitochondrial ADP, ATP Translocases; Nelfinavir; Pancreatitis; Ritonavir; Signal Transduction; Stroke; T-Lymphocytes

There is no clinical treatment that reduces acinar injury during pancreatitis. Human immunodeficiency virus (HIV) protease inhibitors (PI), including nelfinavir (NFV) and ritonavir (RTV), may reduce the rate of pancreatitis in HIV-infected patients. Since permeability transition pore (PTPC)-mediated mitochondrial dysfunction occurs during pancreatitis, and we have shown that PI prevents PTPC opening, we studied its effects in a model of pancreatitis. The effect of NFV plus RTV (NFV/RTV) or vehicle on caerulein-induced pancreatitis in mice was compared by measuring changes in mitochondrial membrane potential in vitro and cytochrome c leakage in vivo. Histological and inflammatory makers were also compared. NFV/RTV improved DiOC6 retention in acini exposed to caerulein in vitro. In vivo NFV prevented cytosolic leakage of cytochrome c and reduced pancreatic acinar injury, active caspase-3 staining, TUNEL-positive acinar cells, and serum amylase (P < 0.05). Conversely, trypsin activity, serum cytokine levels, and pancreatic and lung inflammation were unaffected. NFV/RTV reduces pancreatic injury and acinar cell death in experimental mouse caerulein-induced pancreatitis but does not impact inflammation.

Topics: Amylases; Animals; Apoptosis; Caspase 3; Ceruletide; Cytochromes c; Disease Models, Animal; Drug Therapy, Combination; HIV Protease Inhibitors; Inflammation Mediators; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mitochondria; Necrosis; Nelfinavir; Pancreas; Pancreatitis; Ritonavir; Trypsin

Topics: Acute Disease; Adult; Antiretroviral Therapy, Highly Active; HIV Protease Inhibitors; Humans; Hypertriglyceridemia; Male; Pancreatitis; Pyridines; Pyrones; Ritonavir; Sulfonamides

Topics: Adenine; Adult; Antiretroviral Therapy, Highly Active; Didanosine; Drug Interactions; Female; HIV Infections; Humans; Organophosphonates; Organophosphorus Compounds; Pancreatitis; Ritonavir; Stavudine; Tenofovir

The use of protease inhibitors such as ritonavir to treat HIV-infected individuals has been associated with lipodystrophy, combined hyperlipidemias, and hypertriglyceridemia-induced pancreatitis. We report here on the treatment by plasmapheresis of a HIV-patient who presented with a rapid onset of severe ritonavir-induced hypertriglyceridemia complicated with an acute pancreatitis. A 35-year-old HIV-1 positive male following 3 weeks of ritonavir treatment presented with nausea, abdominal pain, a distended abdomen, and the following laboratory values: amylase (238 U/L), lipase (864 U/L), total cholesterol (27.1 mmol/L), and triglycerides (62.9 mmol/L). Following two plasmaphereses, the levels of total cholesterol, triglycerides, lipase, and amylase declined drastically and the patient was discharged home after 4 days with lipid and pancreatic enzyme levels within the reference range. To our knowledge, this is the first case of pancreatitis due to a PI-induced hyperlipidemia in a HIV-patient treated with plasmapheresis in an acute setting.

Topics: Acute Disease; Adult; HIV Infections; Humans; Hypertriglyceridemia; Male; Pancreatitis; Plasmapheresis; Protease Inhibitors; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Acute Disease; Anti-HIV Agents; Carbamates; Coronary Disease; Dideoxynucleosides; Drug Therapy, Combination; Furans; Hepatitis B; HIV Protease Inhibitors; Humans; Hyperlipoproteinemias; Male; Middle Aged; Pancreatitis; Risk Factors; Ritonavir; Sulfonamides

Topics: Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; Humans; Hypertriglyceridemia; Male; Middle Aged; Pancreatitis; Ritonavir

Topics: Acute Disease; HIV Infections; HIV Protease Inhibitors; Humans; Hypertriglyceridemia; Pancreatitis; Ritonavir; Triglycerides

Topics: Anti-HIV Agents; Coronary Artery Disease; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lipids; Male; Middle Aged; Pancreatic Pseudocyst; Pancreatitis; Risk Factors; Ritonavir; Saquinavir

Topics: Acute Disease; Adult; Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Hypertriglyceridemia; Male; Pancreatitis; Reverse Transcriptase Inhibitors; Ritonavir; Trimethoprim, Sulfamethoxazole Drug Combination; Zidovudine