Gene/Protein Disease Symptom Drug Enzyme Compound
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Use of the commonly prescribed protease inhibitor Crixivan appears to result in a bizarre adverse effect, despite its desirable effects on T-cell count and viral load. This adverse effect is more common in women than men, and includes the following symptoms: (1) limb wasting, (2) fat gain in the torso, (3) breast enlargement, (4) skin thinning, (4) vein enlargement, (5) irregular periods, (6) high blood pressure and high blood glucose, (6) fatigue, and (7) decreased sex drive. It is believed that 5 to 10 percent of patients taking Crixivan suffer from some of these symptoms, but the percentage would probably be much higher if the number of women alone were studied. Some physicians have been unsupportive about complaints of these symptoms, and have told their patients to exercise or that the changes may be due to aging. One suggestion for dealing with these symptoms is to get body composition measurements prior to starting a protease-containing regimen. Exercise continues to remain important, primarily to prevent wasting. However, dieting is not recommended since it does not reduce the fat deposits and it does contribute to wasting of the limbs. If the symptoms become intolerable, a change in regimen may be needed.
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PMID:The new body of AIDS: Crixivan bellies, legs, and humps. 1136 90

We report the case of a 40-year-old HIV-positive man, undergoing three-drug antiretroviral therapy for 2 years that included a protease inhibitor (ritonavir). The patient was admitted to our Coronary Care Unit with an acute anterior myocardial infarction. He smoked 20 cigarettes/day and had a family history of hypertension. At the time of hospitalization, triglyceride levels were found to be high (290 mg/dl). Metabolic alterations associated with the prolonged use of protease inhibitors, such as insulin resistance, dyslipidemia and lipodystrophy, have recently been described. This side effect may lead to premature coronary artery disease. Therefore it is mandatory to be aware that treatment with protease inhibitors in HIV-positive patients, despite survival prolongation and lowering of AIDS complications, may accelerate atherosclerosis and precipitate acute coronary events, especially in patients with pre-existing cardiovascular risk factors.
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PMID:[Acute myocardial infarct in HIV-positive patients in treatment with protease inhibitors]. 1177 17

Subarachnoid haemorrhage (SAH) results from leakage of blood into the subarachnoid space and carries high morbidity and mortality. However, there is limited understanding to date, of the risk factors, cellular, intermediate biochemical and genetic traits predisposing to SAH. Nevertheless, in conjunction with improved methods of diagnostic imaging and less invasive approaches to preventing aneurysmal rupture, there may be utility in gaining a better understanding of the pathogenesis and in identifying pre-disease markers. Additionally, it is not impossible that drugs of value (e.g. matrix or endothelial modifiers) could become available. Several different clinical subtypes can be recognised, distinguished by arterial or venous involvement, presence of unruptured arterial aneurysms, and apparently "sporadic" and "familial" occurrences. Epidemiological risk factors include alcohol consumption and smoking: hypertension is a risk factor for rupture. About 10% seem to reflect strong family history and this subset may be particularly illuminating with respect to the molecular pathogenesis. Haemodynamic stress and poor vascular structure may be the main mechanisms of pathogenesis. The epidemiological and statistical evidence for familial megaphenic genes and modifier genes is reviewed. This review focuses on the pathogenesis, as opposed to inflammatory response to SAH. It sets in context the roles of specific genes and their protein products, such as polycystin (PKD1), fibrillin (FBN1), collagen III (COL3A1), elastin (ELN), collagen IV, protease inhibitor or alpha1-antitrypsin (PI) and proteases. These considerations illustrate the shortfalls in current knowledge, the needs of future biochemical and cellular research and their potential implications for future prevention of this often fatal condition.
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PMID:Molecular pathogenesis of subarachnoid haemorrhage. 1279 48

We report a case of a 38-years-old HIV-positive patient, undergoing in the last 18 months therapy with three antiretroviral drugs including a protease inhibitor (nelfinavir). The patient was admitted in our Department with acute anterior myocardial infarction and was submitted to PTCA on the left anterior descending coronary artery. The patient, a 30 cigarettes/day smoker, with family history of hypertension and high levels of trygliceride and cholesterol, was subsequently admitted to our Cardiac Rehabilitation Unit. Cardiac Rehabilitation Program was composed of cycle aerobic training 4 times/week, dietary education, psychologic support and therapy with pravastatin, aspirin, nitrate, enalapril, and carvedilol. At the end of the 8 week Rehabilitation Program we observed a normalization of cholesterol and trygliceride levels and an improvement of cardiac functional capacity and mental health.
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PMID:[Cardiac rehabilitation in a HIV-patient treated with protease inhibitors]. 1282 39

The distribution of risk factors for cardiovascular disease in patients aged 35-44 years who were treated for human immunodeficiency virus type 1 (HIV-1) infection was compared with that for a population-based cohort. HIV-1-infected men treated with a protease inhibitor-containing regimen (n=223), compared with HIV-1-uninfected men (n=527), were characterized by a lower prevalence of hypertension, a lower mean high-density lipoprotein cholesterol level, a higher prevalence of smoking, a higher mean waist-to-hip ratio, and a higher mean triglyceride level. No difference was found for total plasma or low-density cholesterol levels, nor for the prevalence of diabetes. Similar trends were observed among female subjects. The predicted risk of coronary heart disease was greater among HIV-1-infected men (relative risk [RR], 1.20) and women (RR, 1.59; P<10(-6) for both), compared with the HIV-1-uninfected cohort. The estimated attributable risks due to smoking were 65% and 29% for HIV-1-infected men and women, respectively. Because most HIV-1-infected people will ultimately need antiretroviral therapy, risk factors for cardiovascular disease should be determined at the initiation of treatment, and interventions should be considered for all patients who have them.
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PMID:Risk factors for coronary heart disease in patients treated for human immunodeficiency virus infection compared with the general population. 1285 22

Dyslipidemia, characterized by elevated serum levels of triglycerides and reduced levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol, has been recognized in patients with human immunodeficiency virus (HIV) infection. It is thought that elevated levels of circulating cytokines, such as tumor necrosis factor-alpha and interferon-alpha, may alter lipid metabolism in patients with HIV infection. Protease inhibitors, such as saquinavir, indinavir and ritonavir, have been found to decrease mortality and improve quality of life in patients with HIV infection. However, these drugs have been associated with a syndrome of fat redistribution, insulin resistance, and hyperlipidemia. Elevations in serum total cholesterol and triglyceride levels, along with dyslipidemia that typically occurs in patients with HIV infection, may predispose patients to complications such as premature atherosclerosis and pancreatitis. It has been estimated that hypercholesterolemia and hypertriglyceridemia occur in greater than 50% of protease inhibitor recipients after 2 years of therapy, and that the risk of developing hyperlipidemia increases with the duration of treatment with protease inhibitors. In general, treatment of hyperlipidemia should follow National Cholesterol Education Program guidelines; efforts should be made to modify/control coronary heart disease risk factors (i.e. smoking; hypertension; diabetes mellitus) and maximize lifestyle modifications, primarily dietary intervention and exercise, in these patients. Where indicated, treatment usually consists of either pravastatin or atorvastatin for patients with elevated serum levels of LDL-C and/or total cholesterol. Atorvastatin is more potent in lowering serum total cholesterol and triglycerides compared with other hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, but it is also associated with more drug interactions compared with pravastatin. Simvastatin and lovastatin are significantly metabolized by cytochrome P450 enzymes (CYP3A4) and are therefore not recommended for coadministration with protease inhibitors. A fibric acid derivative (gemfibrozil or fenofibrate) should be used in patients with primary hypertriglyceridemia. However, it must be kept in mind that protease inhibitors, such as nelfinavir and ritonavir, induce enzymes involved in the metabolism of the fibric acid derivatives and may, therefore, reduce the lipid-lowering activity of coadministered gemfibrozil or fenofibrate. In certain patients HMG-CoA reductase inhibitors may be used in combination with fibric acid derivatives but patients should be carefully monitored for liver and skeletal muscle toxicity. Select patients may experience improvements in serum lipid levels when their offending protease inhibitor(s) is/are exchanged for efavirenz, nevirapine, or abacavir; however each patient's virologic and immunologic status must be taken closely into consideration.
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PMID:Management of protease inhibitor-associated hyperlipidemia. 1472 85

The metabolic syndrome is intended to identify patients who have increased risk of diabetes and/or a cardiac event due to the deleterious effects of weight gain, sedentary lifestyle, and/or an atherogenic diet. The National Cholesterol Education Program's Adult Treatment Panel III definition uses easily measured clinical findings of increased abdominal circumference, elevated triglycerides, low high-density lipoprotein-cholesterol, elevated fasting blood glucose and/or elevated blood pressure. Three of these five are required for diagnosis. The authors also note that other definitions of metabolic syndrome focus more on insulin resistance and its key role in this syndrome. This review focuses on how treatment might affect each of the five components. Abdominal obesity can be treated with a variety of lower calorie diets along with regular exercise. Indeed, all of the five components of the metabolic syndrome are improved by even modest amounts of weight loss achieved with diet and exercise. For those with impaired fasting glucose tolerance, there is good evidence that a high fiber, low saturated fat diet with increased daily exercise can reduce the incidence of diabetes by almost 60%. Of note, subjects who exercise the most, gain the most benefit. Metformin has also been shown to be helpful in these subjects. Thiazolidinedione drugs may prove useful, but further studies are needed. Although intensified therapeutic lifestyle change will help the abnormal lipid profile, some patients may require drug therapy. This review also discusses the use of statins, fibrates, and niacin. Likewise, while hypertension in the metabolic syndrome benefits from therapeutic lifestyle change, physicians should also consider angiotensin converting enzyme inhibitor drugs or angiotensin receptor blockers, due to their effects on preventing complications of diabetes, such as progression of diabetic nephropathy and due to their effects on regression of left ventricular hypertrophy. Aspirin should be considered in those with at least a 10% risk of a coronary event over 10 years. Finally, three related conditions, nonalcoholic fatty liver disease, polycystic ovary syndrome and protease inhibitor associated lipodystrophy improve with therapeutic lifestyle change. Although metformin is shown to be useful with polycystic ovary syndrome, the data supporting drug therapy for the other syndromes is less convincing. More robust studies are needed before any firm recommendations can be made.
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PMID:Treatment of metabolic syndrome. 1515 70

The epidemiology of the metabolic complications of antiretroviral agents is discussed here. Contradictory findings are common in this field due to methodological problems. The prevalence depends on the activity of the infection and on the type of treatment. Before treatment, the most common lipid abnormalities are low HDL-cholesterol (< 35 mg/dL, 25.5%) and hypertriglyceridemia (> 200 mg/dL, 15.2%). The prevalence of hypercholesterolemia is 3 times higher during treatment, especially if a protease inhibitor (IP) is used. Hypertension has been described as not common because high thresholds have been used in previous reports. Diabetes has been found in 6-7%. Similar prevalences were found in a retrolective study including 464 cases. Before treatment, hypertriglyceridemia was found mainly in cases with a body weight below normal; the opposite trend was found after treatment. After one year of treatment the prevalence of hypertension (> or = 130/85), hypertriglyceridemia (> or = 150), hypercholesterolemia (> 200 mg/dL), diabetes and low HDL cholesterol (< 35 mg/dL) were 38.5, 71.1, 47.6, 2.2% and 36%, respectively. The frequencies were even greater in IP-treated cases. Smoking was a frequent modifiable risk factor in this group (42.3%). Thus, many aspects remain to be explored; the follow-up of multicentric cohorts will provide evidence for preventive actions. In Mexican HIV infected patients, hypertriglyceridemia, arterial hypertension and smoking are the most common cardiovascular risk factors.
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PMID:[Epidemiology of the metabolic abnormalities in patients with HIV infections]. 1537 74

Toxic nephropathy is an important cause of reversible renal injury. This article focuses on the nephrotoxicity of several new therapeutic compounds. Selective cyclooxygenase-2 inhibitor is associated with sodium retention, hypertension, ankle edema, and acute renal failure. The incidence of renal complication is similar to conventional nonsteroidal anti-inflammatory drugs. Bisphosphonates, especially when used in high dose for prolonged duration, can cause toxic acute tubular necrosis and renal failure. Pamidronate is also associated with a specific form of collapsing focal segmental glomerulosclerosis similar to one found in patients with human immunodeficiency virus (HIV) infection. Acyclic nucleoside phosphonate, a new group of antiviral agents, can cause Fanconi-like syndrome and progressive renal impairment. On the other hand, indinavir, a potent protease inhibitor for the treatment of HIV infection, can cause crystalluria, renal stone, acute tubular obstruction and chronic interstitial nephritis. Intravenous immune globulin and hydroxyethyl starch, a new plasma expander, are associated with acute renal failure with characteristic renal histology known as osmotic nephrosis. In short, physicians should be cautious about possible renal toxicity during the use of any new therapeutic agents.
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PMID:Nephrotoxicity related to new therapeutic compounds. 1595 51

Insulin resistance is accepted as the underlying fundamental defect that predates and ultimately leads to the development of type 2 (adult onset) diabetes mellitus in the general non-human immunodeficiency virus (HIV)-infected population. Insulin resistance is also a major component of the metabolic syndrome that, in association with other factors such as hypertension, hypercholesterolemia, and central obesity, defines a pre-diabetic atherogenic state that leads to adverse cardiovascular events. Growing evidence now suggests that mitochondrial dysfunction in skeletal muscle may be the mechanism whereby insulin resistance is induced. The prevalence of insulin resistance, glucose intolerance, and diabetes in the HIV-infected population has dramatically increased following the common use of highly active antiretroviral therapy (HAART). The development of insulin resistance in the HIV-infected population is likely to be multifactorial reflecting genetic predisposition, direct and indirect effects of both the protease inhibitor (PI) and nucleoside reverse transcriptase inhibitor (NRTI) class of antiretroviral therapy, and a possible contribution from chronic inflammatory changes induced by HIV. Indirect effects of antiretroviral therapy on insulin resistance may be mediated through both the visceral adiposity and peripheral fat depletion components of lipodystrophy as well as through fatty infiltration in liver and muscle. Based on current knowledge, mitochondrial dysfunction can be hypothesized to play a key role in each of these components.
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PMID:Insulin resistance in the HIV-infected population: the potential role of mitochondrial dysfunction. 1618 Nov 44


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