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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of highly active antiretroviral therapy, the combination of at least three different antiretroviral drugs for the treatment of HIV-1 infection, has greatly improved the prognosis for HIV-1-infected patients. The efficacy of a combination of a protease inhibitor (PI) plus two nucleoside analogue reverse transcriptase inhibitors has been well established over a period of up to 3 years. However, virological treatment failure has been reported in 40-60% of unselected patients within 1 year after initiation of a PI-containing regimen. This observation may, at least in part, be attributed to the poor pharmacokinetic characteristics of the PIs. Given as a single agent the PIs have several pharmacokinetic limitations; relatively short plasma-elimination half-lives and a modest and variable oral bioavailability, which is, for some of the PIs, influenced by food. To overcome these suboptimal pharmacokinetics, high doses (requiring large numbers of pills) must be ingested, often with food restrictions, which complicates patient adherence to the prescribed regimen. Positive drug-drug interactions increase the exposure to the PIs, allowing administration of lower doses at reduced dosing frequencies with less dietary restrictions. In addition to increasing the potency of an antiretroviral regimen, combinations of PIs may enhance patient adherence, both of which will contribute to a more durable suppression of viral replication. The favourable pharmacokinetics of PIs in combination are a result of interactions through cytochrome P450 3A4 (CYP3A4) isoenzymes and, possibly, the multi-drug transporting P-glycoprotein (P-gp). Antiretroviral synergy between PIs and non-overlapping primary resistance patterns in the HIV-1 protease genome may further enhance the antiretroviral potency and durability of combinations of PIs. Many combinations contain ritonavir because this PI has the most pronounced inhibiting effects on CYP3A4. The combination of saquinavir and ritonavir, both in a dose of 400 mg twice-a-day, is the most studied double PI combination, with clinical experience extending over 3 years. Combination of a PI with a low dose of ritonavir (< or = 400 mg/day), only to boost its pharmacokinetic properties, seems an attractive option for patients who cannot tolerate higher doses of ritonavir. A recently introduced PI, lopinavir, has been co-formulated with low-dose ritonavir, which allows for a convenient three-capsules, twice-a-day dosing regimen. In an attempt to prolong suppression of viral replication combinations of PIs are becoming increasingly popular. However, further clinical studies are needed to identify the optimal combinations for treatment of antiretroviral naive and experienced HIV-1-infected patients. This review covers combinations of saquinavir, indinavir, nelfinavir, amprenavir and lopinavir with different doses of ritonavir, as well as the combinations of saquinavir and indinavir with nelfinavir.
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PMID:Combination of protease inhibitors for the treatment of HIV-1-infected patients: a review of pharmacokinetics and clinical experience. 1187 3

Clinically significant interactions occurring during antituberculous chemotherapy principally involve rifampicin (rifampin), isoniazid and the fluoroquinolones. Such interactions between the antituberculous drugs and coadministered agents are definitely much more important than among antituberculous drugs themselves. These can be associated with consequences even amounting to therapeutic failure or toxicity. Most of the interactions are pharmacokinetic rather than pharmacodynamic in nature. The cytochrome P450 isoform enzymes are responsible for many interactions (especially those involving rifampicin and isoniazid) during drug biotransformation (metabolism) in the liver and/or intestine. Generally, rifampicin is an enzyme inducer and isoniazid acts as an inhibitor. The agents interacting significantly with rifampicin include anticoagulants, anticonvulsants, anti-infectives, cardiovascular therapeutics, contraceptives, glucocorticoids, immunosuppressants, psychotropics, sulphonylureas and theophyllines. Isoniazid interacts principally with anticonvulsants, theophylline, benzodiapines, paracetamol (acetaminophen) and some food. Fluoroquinolones can have absorption disturbance due to a variety of agents, especially the metal cations. Other important interactions of fluoroquinolones result from their enzyme inhibiting potential or pharmacodynamic mechanisms. Geriatric and immunocompromised patients are particularly at risk of drug interactions during treatment of their tuberculosis. Among the latter, patients who are HIV infected constitute the most important group. This is largely because of the advent of new antiretroviral agents such as the HIV protease inhibitors and the non-nucleoside reverse transcriptase inhibitors in the armamenterium of therapy. Compounding the complexity of drug interactions, underlying medical diseases per se may also contribute to or aggravate the scenario. It is imperative for clinicians to be on the alert when treating tuberculosis in patients with difficult co-morbidity requiring polypharmacy. With advancement of knowledge and expertise, it is hoped that therapeutic drug monitoring as a new paradigm of care can enable better management of these drug interactions.
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PMID:Clinically significant interactions with drugs used in the treatment of tuberculosis. 1188 53

The HMG-CoA reductase inhibitors (statins) are effective in both the primary and secondary prevention of ischaemic heart disease. As a group, these drugs are well tolerated apart from two uncommon but potentially serious adverse effects: elevation of liver enzymes and skeletal muscle abnormalities, which range from benign myalgias to life-threatening rhabdomyolysis. Adverse effects with statins are frequently associated with drug interactions because of their long-term use in older patients who are likely to be exposed to polypharmacy. The recent withdrawal of cerivastatin as a result of deaths from rhabdomyolysis illustrates the clinical importance of such interactions. Drug interactions involving the statins may have either a pharmacodynamic or pharmacokinetic basis, or both. As these drugs are highly extracted by the liver, displacement interactions are of limited importance. The cytochrome P450 (CYP) enzyme system plays an important part in the metabolism of the statins, leading to clinically relevant interactions with other agents, particularly cyclosporin, erythromycin, itraconazole, ketoconazole and HIV protease inhibitors, that are also metabolised by this enzyme system. An additional complicating feature is that individual statins are metabolised to differing degrees, in some cases producing active metabolites. The CYP3A family metabolises lovastatin, simvastatin, atorvastatin and cerivastatin, whereas CYP2C9 metabolises fluvastatin. Cerivastatin is also metabolised by CYP2C8. Pravastatin is not significantly metabolised by the CYP system. In addition, the statins are substrates for P-glycoprotein, a drug transporter present in the small intestine that may influence their oral bioavailability. In clinical practice, the risk of a serious interaction causing myopathy is enhanced when statin metabolism is markedly inhibited. Thus, rhabdomyolysis has occurred following the coadministration of cyclosporin, a potent CYP3A4 and P-glycoprotein inhibitor, and lovastatin. Itraconazole has been shown to increase exposure to simvastatin and its active metabolite by at least 10-fold. Pharmacodynamically, there is an increased risk of myopathy when statins are coprescribed with fibrates or nicotinic acid. This occurs relatively infrequently, but is particularly associated with the combination of cerivastatin and gemfibrozil. Statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring. Knowledge of the pharmacokinetic properties of the statins should allow the avoidance of the majority of drug interactions. If concurrent therapy with known inhibitors of statin metabolism is necessary, the patient should be monitored for signs and symptoms of myopathy or rhabdomyolysis and the statin should be discontinued if necessary.
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PMID:Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. 1203 92

In HIV-infected patients, ritonavir, a potent cytochrome P450 inhibitor, is increasingly used to improve the pharmacokinetic profile of the associated protease inhibitor. HIV physicians are often faced with potential drug-drug interaction while treating associated diseases. We report the case of an HIV-infected patient with clinical features of Cushing's syndrome due to the interaction of low dose ritonavir with inhaled fluticasone propionate (FP). Safety of life-long CYP450 inhibition has still to be demonstrated.
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PMID:Iatrogenic Cushing's syndrome in an HIV-infected patient treated with inhaled corticosteroids (fluticasone propionate) and low dose ritonavir enhanced PI containing regimen. 1209 50

Considerable interpatient variability in indinavir pharmacokinetics, possibly due in part to variable metabolism of the drug through intestinal cytochrome P450 (CYP) 3A4, may contribute to poor virologic response in certain individuals with HIV infection. The purpose of this study was to characterize the influence of intestinal CYP3A4 modulation with grapefruit juice and Seville orange juice on indinavir pharmacokinetics. In an open-label, three-period crossover study, 13 healthy volunteers received indinavir 800 mg every 8 hours for 1 day and a single 800 mg dose the next morning. The last two indinavir doses were taken with 8 ounces of Seville orange juice, single-strength grapefruit juice, or water (control). Plasma samples were collected at time 0 (predose) and at 0.5, 1, 2, 3, 4, and 5 hours after the last indinavir dose. Concentration-time data were analyzed using noncompartmental methods. Coadministration of Seville orange juice and indinavir resulted in a statistically significant increase in indinavir t(max) (1.87 [1.65-2.22] vs. 1.25 [1.03-1.60] h; p < 0.05) without altering other pharmacokinetic parameter values. Grapefruit juice administration did not result in any changes in indinavir pharmacokinetics. Modulation of intestinal CYP3A4 by grapefruit juice and Seville orange juice did not alter the systemic availability of indinavir. The contribution of presystemic metabolism to indinavir interpatient variability appears to be small.
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PMID:Effect of Seville orange juice and grapefruit juice on indinavir pharmacokinetics. 1236 32

Human immunodeficiency virus (HIV) protease inhibitors are prone to drug interactions with other agents. As individuals with HIV infection live longer, the clinical significance of many interactions is becoming recognized. A 51-year-old man with HIV infection who was receiving extended-release nifedipine developed symptomatic orthostasis and heart block after starting antiretroviral therapy that included nelfinavir. He experienced dizziness, fatigue, and hypotension and developed complete heart block with a junctional escape rhythm. Electrocardiogram abnormalities abated within 24 hours of discontinuing antiretroviral therapy. The patient developed orthostatic symptoms after restarting nelfinavir. He was switched successfully to an efavirenz-based regimen. Subsequent administration of antiretroviral therapy containing ritonavir and indinavir with extended-release nifedipine resulted in recurrence of his orthostatic symptoms. Discontinuation of atenolol, and nifedipine dosage reduction by 50% were effective in managing his orthostatic changes. Careful monitoring by clinicians is necessary when concomitant administration of HIV protease inhibitors are prescribed with other agents that are metabolized through the cytochrome P450 system.
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PMID:Symptomatic orthostasis with extended-release nifedipine and protease inhibitors. 1238 81

Treatment of HIV infection with potent combination antiretroviral therapy has resulted in major improvement in overall survival, immune function and the incidence of opportunistic infections. However, HIV infection and treatment has been associated with the development of metabolic complications, including hyperlipidaemia, diabetes mellitus, hypertension, lipodystrophy and osteopenia. Safe pharmacological treatment of these complications requires an understanding of the drug-drug interactions between antiretroviral drugs and the drugs used in the treatment of metabolic complications. Since formal studies of most of these interactions have not been performed, predictions must be based on our understanding of the metabolism of these agents. All HIV protease inhibitors are metabolised by and inhibit cytochrome P450 (CYP) 3A4. Ritonavir is the most potent inhibitor of CYP3A4. Ritonavir and nelfinavir also induce a host of CYP isoforms as well as some conjugating enzymes. The non-nucleoside reverse transcriptase inhibitor delavirdine potently inhibits CYP3A4, whereas nevirapine and efavirenz are inducers of CYP3A4. Drug interaction studies have been performed with HIV protease inhibitors and HMG-CoA reductase inhibitors. Coadministration of ritonavir plus saquinavir to HIV-seronegative volunteers resulted in increased exposure to simvastatin acid by 3059%. Atorvastatin exposure increased by 347%, but exposure to active atorvastatin increased by only 79%. Conversely, pravastatin exposure decreased by 50%. Similar results have been obtained with combinations of simvastatin and atorvastatin with other HIV protease inhibitors. Thus, the lactone prodrugs simvastatin and lovastatin should not be used with HIV protease inhibitors. Atorvastatin may be used with caution. Although there are no formal studies available, calcium channel antagonists and repaglinide may have significant interactions and toxicity when used with HIV protease inhibitors because of their metabolism by CYP3A4. Sulfonylurea drugs utilise mainly CYP2C9 for metabolism, and this isoenzyme may be induced by ritonavir and nelfinavir with a resulting decrease in efficacy of the sulfonylurea. Losartan may have increased effect when coadministered with ritonavir and nelfinavir because of the induction of CYP2C9 and the expected increase in formation of the active metabolite, E-3174. Overall, well-designed drug-drug interaction studies at steady state are needed to determine whether antiretroviral drugs may be safely coadministered with many of the drugs used in the treatment of the metabolic complications of HIV infection.
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PMID:Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. 1240 66

Although not yet recommended, regimens combining both a non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitors (PI) can be used as first-line therapy, or as second-line or salvage therapy in patients who need to change antiretroviral treatment because of nucleoside reverse transcriptase inhibitors (NRTI) intolerance or virological failure with resistance to NRTI. Such combinations should not be used in patients infected with HIV-1 group O and HIV-2, due to the natural resistance to NNRTI of these subtypes. Dual NNRTI and PI combinations used as first-line therapy allow to spare NRTI, leaving a fully active class of drugs for later use, and delaying the risk of toxicity related to NRTI exposure, particularly mitochondrial toxicity. Several studies have shown that adding a NNRTI improves the efficacy of a second-line or salvage therapy based on a new combination of PI(s) and new or recycled NRTI(s). A possible explanation for the efficacy of NNRTI-containing regimens in NRTI-pretreated patients is that mutations conferring resistance to NRTI can increase the susceptibility of the viruses to the NNRTI. However, the decision to use a NNRTI in a salvage regimen needs to be weighed against the concern that subsequent failure will exhaust therapeutic options with any compound of this class, due the large degree of cross-resistance between the three available NNRTI. NNRTI and PIs are extensively metabolized in the liver through cytochrome P450, leading to pharmacokinetic interactions. The decrease in PIs plasma concentrations observed when they are combined with nevirapine or efavirenz is reduced when low doses of ritonavir, which strongly inhibits cytochrome P450, are associated with the combination of PI and NNRTI.
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PMID:NNRTI plus PI combinations in the perspective of nucleoside-sparing or nucleoside-failing antiretroviral regimens. 1241 47

The present study evaluated the effect of cimetidine, a histamine H(2) receptor antagonist able to inhibit cytochrome P450 metabolism, on the steady-state pharmacokinetics of saquinavir soft gel. Twelve healthy volunteers (eight males and four females) participated in an open-label, double-phase pharmacokinetic study. Volunteers took saquinavir soft gel 1200 mg three times a day for 13 days and then saquinavir soft gel 1200 mg twice a day with cimetidine 400 mg twice a day from day 14 to 26. The pharmacokinetics of saquinavir on days 13 and 26 were compared. All 12 volunteers completed the study. The association of cimetidine with saquinavir soft gel 1200 mg twice a day resulted in a significant increase in saquinavir AUC(0-24) (120%; P = 0.023) and C(max) (179%; P = 0.019), whereas C(trough) did not differ significantly (32% increase; P = 0.272). Increased exposure to saquinavir was observed in healthy volunteers after co-administration with cimetidine. The most significant increase involved C(max). Further pharmacokinetic studies in HIV-infected subjects are warranted to confirm the boosting effect of cimetidine and to investigate any impact that the increase in saquinavir C(max) may have on intracellular accumulation of the drug.
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PMID:Pharmacokinetics of saquinavir co-administered with cimetidine. 1246 Oct 38

Low doses of ritonavir, a strong inhibitor of cytochrome P450 3A4, enhances the pharmacokinetic profile of indinavir with increased serum levels. We assessed the indinavir-ritonavir 400/200 twice daily combination in 17 HIV-infected patients focusing on the pharmacokinetic data and the tolerance of this regimen. IDV trough and peak concentrations were measured by high-performance liquid chromatography. Median indinavir trough and peak concentrations were 553 ng/ml and 3626 ng/ml, respectively. A good tolerance was observed except for three patients who experienced a major toxicity. Only one dose adjustment was related to indinavir toxicity. Considering the fact that Cmax is mainly responsible of the adverse effects, particularly renal stones, the indinavir-ritonavir 400/200 mg twice daily regimen offers a well-tolerated combination with an increased Cmin but a lower Cmax compared with both the standard tid regimen and higher dose of IDV-RTV regimens.
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PMID:Experience of a combination including indinavir 400 mg plus ritonavir 200 mg twice daily in HIV-infected patients: pharmacokinetic data. 1249 Apr 21


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