Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Itraconazole is a synthetic triazole antifungal agent that is commonly used in the prophylaxis and treatment of fungal infection. A role for itraconazole drug monitoring has been suggested previously; however, the advent of new formulations and increased clinical evidence may aid in further defining this role. Consequently, we have used a previously published decision-making algorithm to determine whether clinical pharmacokinetic monitoring of itraconazole is warranted. First, itraconazole has proven efficacy for the prophylaxis and treatment of fungal infection in immunocompromised individuals such as neutropenic cancer, human immunodeficiency virus (HIV), and solid organ transplant patients. Several assays have been developed to quantify itraconazole and its main metabolite in patient plasma. Measurement of these plasma drug levels in many clinical studies has resulted in no clear definition of a relationship between concentration and efficacy. However, limited evidence suggests a correlation between itraconazole levels greater than 250 or 500 ng/mL and increased efficacy. Clinical monitoring of efficacy is difficult because of the challenges in diagnosis of fungal infections and nonspecific clinical symptoms associated with fungal infections. Pharmacokinetic studies of itraconazole indicate that significant inter- and intrapatient variability exists in both healthy and immunocompromised patient populations, although subpopulations such as neutropenic cancer and HIV patients appear to require more drug than their healthy counterparts to attain similar drug levels. A therapeutic range has not been defined for itraconazole, but because of its relatively minimal side effects, a narrow range is unlikely. Drug interactions can occur with itraconazole because it is both an inhibitor and substrate of the cytochrome P450 3A4 (CYP3A4) enzyme and P-glycoprotein transporter systems. Protein binding alterations could also lead to differences in drug effect. Last, the duration of treatment of prophylaxis is significantly long to propose a potential benefit from drug monitoring. From weighing the available evidence, it appears that itraconazole drug level monitoring would provide more information on efficacy than clinical judgment alone in a subset of patients. Immunosuppressed patients requiring preventative therapy who have suspected poor absorption, are on concomitant enzyme inducers, or are suspected to be noncompliant would have the greatest benefit from itraconazole drug monitoring.
Ther Drug Monit 2005 Jun
PMID:Clinical pharmacokinetic monitoring of itraconazole is warranted in only a subset of patients. 1590 3

Acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV) that is characterized by profound immunodeficiency, opportunistic infections and Kaposi's sarcoma. As yet no effective therapy is available for AIDS, though retroviral drugs are able to prolong life and contain HIV proliferation to some extent. I propose that essential fatty acids (EFAs) and their metabolites could be useful in the prevention and management of AIDS. Linoleic acid (LA) and arachidonic acid (AA) inactivate enveloped viruses, linolenic acid-enriched macrophages are markedly tumoricidal, EFAs activate macrophages and neutrophils and induce free radical generation; and cytokines bring about some of their actions by inducing the release of EFAs; gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA) prevent genetic damage and have tumoricidal actions as well; and are relatively non-toxic when administered orally or parentarally over long periods of time. In view of this, I suggest that further studies with regard to the role of GLA, AA, EPA and/or docosahexaenoic acid (DHA) in the pathobiology of AIDS needs to be performed. It is also proposed that possible use of these fatty acids in the prevention and treatment of AIDS needs serious consideration.
Med Sci Monit 2005 Jun
PMID:Essential fatty acids and acquired immunodeficiency syndrome. 1591 32

The influence of saquinavir hard-gel capsules on lopinavir pharmacokinetic parameters was investigated using a population approach. Forty-nine patients infected with human immunodeficiency virus type 1 and treated with lopinavir/ritonavir, nucleoside/nucleotide reverse transcriptase inhibitors plus saquinavir (group A), and 118 patients treated with lopinavir/ritonavir plus nucleoside/nucleotide reverse transcriptase inhibitors (group B) were included in the study. No significant relationship was established between the presence or the daily dosage of saquinavir in the treatment and lopinavir population pharmacokinetic parameters. The values (mean+/-standard deviation) of the individual apparent clearance (5.0+/-1.8 vs. 5.0+/-3.2 L/h), volume of distribution (66.6+/-1.6 vs. 66.8+/-1.9 L), absorption rate constant (0.37+/-0.01 vs. 0.37+/-0.03 hours), and trough plasma concentration (5.5+/-2.3 vs. 5.3+/-1.9 mg/L) of lopinavir are not significantly different between groups A and B. This lack of influence of saquinavir on lopinavir pharmacokinetics makes the use of this combination in salvage therapy easier.
Ther Drug Monit 2005 Dec
PMID:No significant influence of saquinavir hard-gel capsule administration on pharmacokinetics of lopinavir in combination with ritonavir: a population approach. 1630 55

The most prominent theory describes the Crohn's Syndrome as a dysregulated, inappropriate immune response to otherwise innocuous bowel flora in a genetically susceptible host. The autoimmune theory assumes that a specific infectious agent does not exist. Data from mouse models, impairment of the mucosal epithelial barrier and the influence of gut flora are used to support the autoimmune theory. Critics claim that the dysregulated immune responses are not the primary disorder but secondary to an underlying infection. Two other theories are also consistent with the same data. The immunodeficiency theory hypothesizes that defects in innate immunity leading to compensatory immune processes underlie the Crohn's phenotype and suggests that therapy should stimulate immunity rather than suppress it. The mycobacterial theory proposes that Mycobacterium avium subspecies paratuberculosis is one of the causes of the Crohn's Disease syndrome. Mycobacterial molecules dysregulate immune signaling pathways as part of the organisms'evolved survival strategy. If MAP were to initiate the dysregulated immune response then the necessity to hypothesize that commensal gut flora provide the antigenic stimulus would be moot. Commensal bacteria would be relegated to a secondary role of modifying the immune response rather than occupying the central role of providing the initiating antigens. Critics claim that MAP is merely a secondary invader. The three theories differ primarily by emphasizing different aspects of the same overall process.
Med Sci Monit 2006 Feb
PMID:Integrating theories of the etiology of Crohn's disease. On the etiology of Crohn's disease: questioning the hypotheses. 1664 83

The concentrations of lopinavir and ritonavir in seminal and blood plasma and the seminal human immunodeficiency virus (HIV) viral load were quantified by HPLC and the Nuclisens assay, respectively, in a cross-sectional study of 16 HIV-1-infected Brazilian men under stable treatment with a lopinavir/ritonavir containing antiretroviral regimen. Semen and blood samples were collected on 2 occasions: at 6 to 60 minutes before ("trough"), and 5 to 6 hours after ("peak") ingestion of regular doses of lopinavir/ritonavir. Median seminal lopinavir levels were 120.6 ng/mL (range, <20-1481.8 ng/mL) and 233.1 ng/mL (range, 48.4-1133.4 ng/mL) at trough and peak points, respectively. The corresponding values for ritonavir were 9.2 ng/mL (range, <5-47 ng/mL) and 17.1 ng/mL (range, 6.6-66.7 ng/mL). The median concentrations of lopinavir and ritonavir in semen were, respectively, 1.9% to 3% and 3.7% to 4.4% of those measured in blood plasma samples collected within 30 minutes. HIV-1 viral load was detectable in the semen of 2 and in the blood of 6 of 16 patients. These results may have implications for drug-resistant HIV-1 evolution and transmission.
Ther Drug Monit 2006 Apr
PMID:Limited penetration of lopinavir and ritonavir in the genital tract of men infected with HIV-1 in Brazil. 1662 27

A case of nephrotic syndrome treated with associated cyclophosphamide and corticosteroids came to our attention after over 2 years of self-administered immunosuppressive therapy which remained unchanged and uncontrolled during this period. The self-administered therapy resulted in a severe cell-mediated immunodeficiency (as expressed by a nadir CD4 lymphocyte count of 2 cells/muL). This led to a rapid unfavorable progression of hepatitis B, which was recently acquired and subsequently evolved into a severe cholestatic and fibrosing chronic hepatitis, causing multiple end-organ failure, and ultimately, death. This process was not reversed by lamivudine therapy, hemodialysis, and the use of a Molecular Adsorbent Recirculating System. The role played by repeated drug prescriptions from general practitioners without appropriate clinical and laboratory controls, and that of our patient's depression are discussed. Current literature related to the presented case and the ongoing debate regarding repeated prescriptions are considered in this study.
Ther Drug Monit 2006 Jun
PMID:Fatal long-term immunosuppressive therapy with uncontrolled repeat prescription. 1677 35

Atazanavir (ATV) is a widely used human immunodeficiency virus (HIV)-1 protease inhibitor (PI) that, like other approved PIs, has been considered as a candidate for therapeutic drug monitoring (TDM). To provide ATV assay results that can be applied to patient management through TDM, the assay would need to perform in a manner consistent with Clinical Laboratory Improvement Amendments (CLIA) standards. To quantitate ATV concentrations in human plasma, the authors added ATV to a previously published reversed-phase high-performance liquid chromatography (HPLC) method from their laboratory. Detection was effected with use of a photodiode-array detector (PDA) collecting spectra at 248 nm. This method allows for detection of ATV to a lower limit of quantitation of 0.05 microg/mL, with an intra-assay coefficient of variation (CV%) of 8.9% or less over 5 days of testing and an interassay CV% ranging from 1.4 to 6.4%. The assay has met passing requirements for interlaboratory proficiency testing for 2 years nationally and internationally, with accuracy within +/-15% over all test samples. During 2 years, more than 100 batches of analyses have been performed and have proved the method is rugged, specific, and accurate. This assay method is currently used in the authors' clinical research program in TDM.
Ther Drug Monit 2007 Feb
PMID:Integration of atazanavir into an existing liquid chromatography UV method for protease inhibitors: validation and application. 1730 57

The efficacy of low-dose, ritonavir-boosted saquinavir (SQV/rtv) once daily plus 2 nucleoside retrotranscriptase inhibitors (NRTIs) in pregnant human immunodeficiency virus (HIV)-1-infected women was prospectively evaluated, ensuring a SQV minimum concentration (Cmin) >/=100 ng/mL with a therapeutic drug monitoring strategy. The primary clinical endpoint was the percentage of women with an HIV-RNA viral load (VL) of <50 copies/mL at the time of delivery. Forty-nine pregnancy episodes were included, with a median CD4 count and VL of 441/muL and 3710 copies/mL, respectively. Two patients were lost to follow-up and 1 patient discontinued treatment because of abdominal discomfort. SQV levels were in excess of the target Cmin in 43 of 46 episodes (93.4%) in which the end of pregnancy was reached on 1200/100 mg daily. The dosage was increased to 1600/100 mg in the remaining 3 episodes to achieve the target levels. By an intention-to-treat analysis, VL was undetectable at delivery in 43 episodes (87.7%; 95% confidence interval, 78.5-96.9) after a median of 18 weeks of treatment (range, 3-39). In the 3 episodes remaining, VLs of 110,400 copies/mL and no available data were observed after only 3 weeks of treatment. Mild adverse events attributable to SQV/rtv occurred in 6 of 49 pregnancies (12.2%). No cases of HIV vertical transmission were observed. The pharmacokinetics, efficacy, and tolerability of this regimen suggest that once-daily low-dose boosted SQV may be considered an appropriate option in PI-naive or limited-PI-experienced HIV-infected pregnant women. Nevertheless, therapeutic drug monitoring is advisable to maintain appropriate levels throughout pregnancy.
Ther Drug Monit 2007 Apr
PMID:Efficacy of low-dose boosted saquinavir once daily plus nucleoside reverse transcriptase inhibitors in pregnant HIV-1-infected women with a therapeutic drug monitoring strategy. 1741 70

Area under the concentration time curve (AUC) over a dosing interval is considered to be the best estimate of drug exposure in a patient. However, determination of this parameter is costly and often impractical, requiring multiple samples and a great deal of time and resources. A limited-sampling strategy (LSS) may overcome some of these issues, making pharmacokinetic studies easier to perform, particularly in a limited-resource setting. The aim of this work was to develop and validate a pragmatic LSS for the accurate and precise prediction of boosted saquinavir AUC0-12 (AUC over the 12-hour dosing interval) at a dosage of 1000/100 mg twice daily. Pharmacokinetic data were obtained from 34 human immunodeficiency virus (HIV)-infected individuals stable on saquinavir/ritonavir-containing therapy, randomly split into two sets (n = 17 per set). One set was used to construct prediction models using univariate and multivariate analysis (development set), and the second was used to determine the predictive performance of the models (validation set). For single samples, 6- and 10-hour concentrations correlated best with saquinavir AUC0-12 (r2: 0.913 and 0.911, respectively), yet all single samples failed to produce precise and unbiased predictions. However, combinations at 2, 6; 0, 2, 6; 0, 4, 10; 0, 4, 12; and 2, 4, 6 hours achieved good predictive performances, and both precise [root mean squared relative prediction error (%RMSE): 6.4% to 11.9%] and unbiased [mean relative prediction error (%MPE), 95% CI: -2.7%, (-0.8)-2.7 to 1.6%, (-1.8)-4.7] estimations of saquinavir AUC0-12. Of these models, concentrations obtained at 0, 2, 6 and 2, 4, 6 hours are more practical in a clinical setting and are therefore the LSS with most potential. Provided that the technique is validated in specific patient populations, an LSS approach is a potentially useful tool to evaluate the AUC0-12 of saquinavir in resource-limited settings, reducing both costs and volumes of blood taken. It may also aid the choice of sampling times for population analysis.
Ther Drug Monit 2007 Jun
PMID:Limited-sampling strategy for the prediction of boosted hard-gel saquinavir exposure at a dosage of 1000/100 mg twice daily in human immunodeficiency virus-infected individuals. 1752 95

Antiretroviral drug measurements as part of therapeutic drug monitoring are performed in several human immunodeficiency virus (HIV) clinics in developed as well as developing countries. Heparin is routinely used as an anticoagulant for plasma drug estimations. EDTA plasma for drug estimations, if found suitable, would have several practical advantages. In this study, plasma nevirapine (NVP) and efavirenz (EFV) levels were compared in paired blood collected in heparin and EDTA Vacutainer tubes (Greiner Bio-one, Austria). The study involved HIV-infected individuals who were receiving antiretroviral treatment at the Government Hospital of Thoracic Medicine, Tambaram, Chennai, India. Their treatment consisted of administration of NVP or EFV, along with lamivudine and stavudine/zidovudine. Blood was collected at the same time in heparin and EDTA Vacutainer tubes. Plasma concentrations of NVP and EFV were estimated, according to validated methods, by high-performance liquid chromatography (HPLC). The mean NVP concentrations in heparin and EDTA plasma were 8.79 and 8.59 microg/mL, respectively. This difference was not statistically significant (P = 0.203). In the case of EFV, the corresponding values were 3.03 and 2.78 microg/mL, respectively; the difference was significant (P < 0.05). However, the percent variation in EFV between both types of plasma was <10%. Blood collected in heparin or EDTA Vacutainer tubes could be used for plasma NVP determination.
Ther Drug Monit 2007 Oct
PMID:Effect of anticoagulants on plasma nevirapine and efavirenz concentrations. 1789 59


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