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)

The pharmacokinetics and bioavailability of adefovir [9-[2-(phosphonomethoxy)ethyl]adenine] were examined at two dose levels in three phase I/II studies in 28 human immunodeficiency type 1-infected patients. The concentrations of adefovir in serum following the intravenous infusion of 1.0 or 3.0 mg/kg of body weight were dose proportional and declined biexponentially, with an overall mean +/- standard deviation terminal half-life of 1.6 +/- 0.5 h (n = 28). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 12 h, and more than 98% was recovered by 24 h postdosing. The overall mean +/- standard deviation total serum clearance of the drug (223 +/- 53 ml/h/kg; n = 25) approximated the renal clearance (205 +/- 78 ml/h/kg; n = 20), which was significantly higher (P < 0.01) than the baseline creatinine clearance in the same patients (88 +/- 18 ml/h/kg; n = 25). Since adefovir is essentially completely unbound in plasma or serum, these data indicate that active tubular secretion accounted for approximately 60% of the clearance of adefovir. The steady-state volume of distribution of adefovir (418 +/- 76 ml/kg; n = 28) suggests that the drug was distributed in total body water. Repeated daily dosing with adefovir at 1.0 mg/kg/day (n = 8) and 3.0 mg/kg/day (n = 4) for 22 days did not significantly alter the pharmacokinetics of the drug; there was no evidence of accumulation. The oral bioavailability of adefovir at a 3.0-mg/kg dose was < 12% (n = 5) on the basis of the concentrations in serum or 16.4% +/- 16.0% on the basis of urinary recovery. The subcutaneous bioavailability of adefovir at a 3.0-mg/kg dose was 102% +/- 8.3% (n = 5) on the basis of concentrations in serum or 84.8% +/- 28.5% on the basis of urinary recovery. These data are consistent with preclinical observations in various species.
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PMID:Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients. 858 16

We examined the pharmacokinetics of ganciclovir in different populations of cytomegalovirus (CMV)-infected patients through the use of nonlinear mixed-effects modelling. As expected, patient weight and estimated creatinine clearance were shown to be important covariates in the serum ganciclovir clearance. Unexpectedly, major differences in ganciclovir clearance between different populations of patients were found. Human immunodeficiency virus (HIV)-infected patients with CMV retinitis cleared ganciclovir 41% faster than HIV-infected patients only shedding CMV into the urine. Solid-organ transplant patients had a serum clearance one-fourth that of HIV-infected patients, even with correction for creatinine clearance. These findings require prospective validation and may have important implications for ganciclovir dosing in different populations of CMV-infected patients.
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PMID:Population differences in ganciclovir clearance as determined by nonlinear mixed-effects modelling. 861 96

The purpose of this study was to determine the safety and pharmacokinetics of lamivudine (3TC), a nucleoside analog that has shown potent in vitro and recent in vivo activity against human immunodeficiency virus. Sixteen human immunodeficiency virus-infected patients, six with normal renal function (creatinine clearance [CLCR], > or = 60 ml/min), four with moderate renal impairment (CLCR, 10 to 40 ml/min), and six with severe renal impairment (CLCR, < 10 ml/min), were enrolled in the study. After an overnight fast, patients were administered 300 mg of 3TC orally. Blood was obtained before 3TC administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, and 48 h afterward. Timed urine collections were performed for patients able to produce urine. Serum and urine were assayed for 3TC by reverse-phase high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were calculated by using standard noncompartmental techniques. The peak concentration of 3TC increased with decreasing renal function; geometric means were 2,524, 3,538, and 5,684 ng/ml for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively. The terminal half-life also increased with decreasing renal function; geometric means were 11.5, 14.1, and 20.7 h for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively. Both oral and renal clearances were linearly correlated with CLCR. A 300-mg dose of 3TC was well tolerated by all three patient groups. The pharmacokinetics of 3TC is profoundly affected by impaired renal function. Dosage adjustment, by either dose reduction or lengthening of the dosing interval, is warranted.
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PMID:Pharmacokinetics of lamivudine in human immunodeficiency virus-infected patients with renal dysfunction. 872 29

The use of the nonparametric expectation maximization (NPEM2) program to estimate pharmacokinetic parameters of ganciclovir in a group of patients with human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infection was evaluated. A 10-point data set per patient obtained over 8 hours was analyzed. Mean pharmacokinetic parameters obtained included rate constant from the central to the peripheral compartment (KCP,3.1 hr-1), rate constant from the peripheral to the central compartment (KPC, 0.824 hr-1), slope of the volume of distribution to body weight (VS, 0.246 L/kg), and slope of clearance to creatinine clearance (Cl(cr)) and body weight (CLS,0.222L/hr/kg/100 mL/ min Cl(cr). Use of NPEM2 led to identification of a subset of patients with CMV retinitis who had a more rapid clearance of ganciclovir of 0.51 to 0.54 L/hr/kg/100 mL/min Cl(cr). Use of smaller, optimally timed samples of five, four, and three data points per patient produced mean pharmacokinetic parameter results consistent with the full ten-point data set. When Bayesian-derived parameter estimates using a five-point data set were compared with a traditional, nonlinear, least-square analysis of the entire ten-point data set, estimates of clearance were determined to be relatively unbiased and precise. The ability of NPEM2 to estimate pharmacokinetic parameters and to determine the population distribution of the parameters was demonstrated. By using points in the analysis chosen by D-optimal design theory, NPEM2 was able to give consistent parameter estimates with as few as three data points. Determination of the distribution appeared to have been dependent on the time points used, however. The approach of MAP-Bayesian analysis to derive patient-specific estimates using optimal samples and prior estimates from a previous population pharmacokinetic analysis for inclusion in subsequent pharmacodynamic analyses of drug exposure (area under the concentration-time curve) may enable development of exposure-response and exposure-toxicity relationships.
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PMID:Nonparametric expectation maximization population modeling of ganciclovir. 872 43

The pathogenesis of human immunodeficiency virus-associated nephropathy (HIVAN) is unknown, but it is characterized by aggressive glomerulosclerosis, tubulopathy, and interstitial inflammation. Currently, no therapy has been proven effective for HIVAN. Angiotensin II has been implicated in the pathogenesis of progressive renal disease in the absence of HIV infection, and treatment with captopril enhances renal survival in patients with diabetic glomerulosclerosis. Serum angiotensin-converting enzyme levels are elevated in patients with HIV infection. We therefore compared the course of 18 patients with biopsy-proven HIVAN (nine treated three times per day with captopril and nine not treated [controls]). The controls were matched to the study patients by age, race, gender, and level of serum creatinine concentration. Renal survival was measured from time of biopsy and treatment with captopril until onset of therapy for end-stage renal disease. Differences between the groups' survival were assessed by Kaplan-Meier and Cox regression analyses. Seven African-American men and two women were in the captopril-treated group, and eight African-American men and one woman were in the control group. No control patient died before the initiation of dialysis. There was no difference between initial mean serum creatinine concentration (3.4 +/- 0.7 mg/dL v 3.7 +/- 0.5 mg/dL), CD4 count (66 +/- 27/microL v 92 +/- 15/microL), or age (41.4 +/- 4.1 years v 36.4 +/- 2.6 years) in the study patients and controls, respectively, but the mean urinary protein to creatinine ratio was higher in the study patients. Renal survival was enhanced in the patients compared with the controls (mean renal survival, 156 +/- 71 days v 37 +/- 5 days, respectively; curves different; P < 0.002, Mantel-Cox log-rank test). Captopril and antiretroviral therapy were associated with enhanced renal survival in a Cox regression analysis, while age, level of serum creatinine, urinary protein to creatinine ratio, and CD4 count were not. These data suggest that treatment with captopril and antiretroviral therapy might be useful in delaying the rapidly progressive renal failure characterizing HIVAN. Captopril might exert its effects by reducing angiotensin II levels, or, alternatively, through decreasing renal tissue expression of growth factors and cytokines or by affecting HIV protease activity and therefore extent of productive renal infection. Such findings must be confirmed by randomized, double-blind, placebo-controlled trials.
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PMID:Captopril and renal survival in patients with human immunodeficiency virus nephropathy. 876 14

A 43-year-old man with rapidly evolving renal failure from biopsy-proven human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) and superimposed thrombotic microangiopathic changes was treated with prednisone. His serum creatinine decreased from 7.5 to 3.9 mg/dL, and the 24-hour protein excretion decreased from 15.7 to 6.1 g over 6 to 8 weeks. As the prednisone was tapered, however, the creatinine began to increase, and a repeat biopsy was done to assist with therapeutic decisions. The major differences from the pretreatment biopsy were marked reductions in interstitial lymphocytes and macrophages and absence of thrombotic microangiopathic lesions. This is the first report comparing pretreatment and posttreatment renal biopsy specimens and the findings provide some insight into the means by which prednisone exerts its beneficial clinical effects acutely on this disease.
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PMID:Clinicopathologic correlates of prednisone treatment of human immunodeficiency virus-associated nephropathy. 884 Sep 56

Accurate assessment of proteinuria in pediatric patients infected with the human immunodeficiency virus (HIV) is limited by constraints imposed by timed urine collections and low creatinine excretion in very ill patients with low muscle mass. We therefore sought to validate the use of random urine specimens to quantitate total protein and creatinine excretion in a population of 236 HIV-positive children. A mathematical derivation for estimating urine volume (V) was constructed. The accuracy of the final calculation [V = 832 (kL/Ucr)BSA] (where k = constant, L body length, UCr urine creatinine and BSA body surface area) was tested by regression analysis comparing the calculated and measured volume of 31 urines from ambulatory HIV-negative patients. The correlation coefficient was highly significant (r = 0.77, P < or = 0.0001). The relationship was also applied to 23 timed urine specimens from HIV-positive patients with similar significance (r = 0.87, P < 0.0001). A regression analysis of measured proteinuria against the urine protein: creatinine ratio (Upr/Ucr) in these same urines from the HIV-positive patients yielded a significant relationship both in the linear (r = 0.95, y = 0.4x) and the logarithmic regression (r = 0.97, y = x + 0.4). These data support the use of random Upr/Ucr ratios to estimate daily proteinuria in HIV-infected pediatric patients despite low creatinine excretion rates. The previously accepted values continue to apply, with Upr/Ucr < or = 2.0 considered normal and > 2.0 representative of nephrotic proteinuria.
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PMID:Validity of random urines to quantitate proteinuria in children with human immunodeficiency virus nephropathy. 889 64

The acquired immunodeficiency syndrome (AIDS) wasting syndrome is a devastating complication of human immunodeficiency virus (HIV) infection characterized by progressive weight loss and severe inanition. In men, the wasting syndrome is characterized by a disproportionate decrease in lean body mass and relative fat sparing. In contrast, relatively little is known about the gender-specific changes in body composition that characterize AIDS wasting in women. Three groups of women were studied to determine body composition and hormonal changes with respect to stage of wasting [nonwasting (NW; weight >90% ideal body weight; weight loss <10% of preillness maximum; n = 12), early wasting (EW; weight >90% ideal body weight; weight loss >10% of preillness maximum; n = 10), and late wasting (LW; weight <90%; n = 9)] and compared with a control group of 12, healthy, age-matched women. Weight loss averaged 6 +/- 6% (NW), 15 +/- 6% (EW), and 20 +/- 8% (LW) in the three groups. Lean, fat, and muscle masses were determined by dual energy x-ray absorptiometry and urinary creatinine excretion. Subjects were 36 +/- 5 yr of age (mean +/- SD) with a CD4 cell count of 379 +/- 239 cells/mm3. The body mass index was 24.4 +/- 2.6 kg/m2 (NW), 22.2 +/- 1.2 kg/m2 (EW), 18.2 +/- 2.0 kg/m2 (LW), and 24.3 +/- 2.6 kg/m2 (controls; P < 0.01, NW vs. EW; P < 0.0001, NW vs. LW). Lean body mass indexed for height was 15.7 +/- 2.4 kg/m2 (NW), 14.8 +/- 2.0 kg/m2 (EW), and 13.7 +/- 1.2 kg/m2 (LW) and was decreased significantly only in the LW group (P < 0.05 vs. NW). Muscle mass was 96% (NW), 94% (EW), and 78% (LW) of that predicted for height (P < 0.05, NW vs. LW). In contrast, fat mass indexed for height was decreased significantly among patients in both the EW and LW groups [8.7 +/- 1.9 kg/m2 (NW), 6.5 +/- 1.9 kg/m2 (EW), and 3.7 +/- 1.4 kg/m2 (LW); P < 0.05, NW vs. EW; P < 0.001, NW vs. LW). Expressed as a percentage of the value in nonwasting HIV-positive controls (NW), the relative loss of fat was greater than the loss of lean mass with progressive degrees of wasting [EW, 25% vs. 6% (fat vs. lean); LW, 58% vs. 13%]. The prevalence of amenorrhea was 20% among study subjects [17% (NW), 10% (EW), and 38% (LW)]. The percent predicted muscle mass was significantly lower in subjects with amenorrhea (74 +/- 8%) compared to that in eumenorrheic HIV-positive subjects (94 +/- 4%; P < 0.05). Estradiol levels were lower among subjects with amenorrhea (17.6 +/- 21.8 pg/mL) compared to eumenorrheic HIV-positive (48.9 +/- 33.6 pg/mL) and control (68.3 +/- 47.6 pg/mL) subjects and did not correlate with body composition. Mean free testosterone, but not total testosterone, levels were decreased in subjects with EW and LW compared to those in age-matched healthy controls, but not compared with those in NW [0.9 +/- 0.6 ng/dL (NW), 0.7 +/- 0.4 ng/dL (EW), 0.6 +/- 0.3 ng/dL (LW), and 2.0 +/- 2.4 ng/dL (controls); P < 0.05, EW vs. controls and LW vs. controls] and correlated with muscle mass (r = 0.37; P < 0.05). The percentages of women with free testosterone levels below the age-adjusted normal range were 33% (NW), 50% (EW), and 66% (LW). Dehydroepiandrosterone sulfate levels were also low in the subjects with LW compared to those in the control group [98 +/- 85 microg/dL (NW), 102 +/- 53 microg/dL (EW), 55 +/- 46 microg/dL (LW), and 132 +/- 68 microg/dL (controls); P < 0.05 LW vs. controls] and were correlated highly with free testosterone levels (r = 0.73; P < 0.00001) and also with muscle mass (r = 0.48; P < 0.01). These data demonstrate that women lose significant lean body and muscle mass in the late stages of wasting. However, in contrast to men, women exhibit a progressive and disproportionate decrease in body fat relative to lean body mass at all stages of wasting, consistent with gender-specific effects in body composition in AIDS wasting. (ABSTRACT TRUNCATED)
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PMID:Body composition and endocrine function in women with acquired immunodeficiency syndrome wasting. 914 12

The use of conventional amphotericin B is limited by toxicity, side-effects, drug interactions and the need for large infusion volumes, especially for infants. Use of liposomal amphotericin B (AmBisome) in 15 paediatric BMT patients with primary immunodeficiency (PID) was therefore studied. Adverse clinical reactions to AmBisome and biochemical profiles were monitored daily for 2 weeks before, during and after each treatment episode. Fungal cultures were obtained weekly and when patients were pyrexial. There were 18 treatment episodes. Mean daily dose was 5 mg/kg (2-6 mg/kg). Mean duration of treatment was 25 days (5-90 days). Clinical reactions to AmBisome were observed in one infant who had a pyrexia of 38 degrees C. One of the 15 infants had a significant increase in creatinine level while on concomitant nephrotoxic therapy. Four developed mild hypokalaemia on AmBisome which resolved with increased potassium supplementation. AmBisome was well tolerated and without significant renal or hepatic toxicity in severely ill immunodeficient infants receiving multiple nephrotoxic and hepatotoxic drugs such as cyclosporin, vancomycin and foscarnet.
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PMID:Liposomal amphotericin (AmBisome) is safe in bone marrow transplantation for primary immunodeficiency. 920 17

This study aimed to determine the stability (in terms of covariate selection) of a population pharmacokinetic model and evaluate its performance in the absence of a test data set. Data from 88 full-term infants, 11 of whom were human immunodeficiency virus (HIV)-seropositive, taking an antiinfective agent were analyzed using exploratory data analysis methods and the nonlinear mixed-effects modeling (NONMEM) program to obtain the final population pharmacokinetic model. The stability of the population pharmacokinetic model was tested using the nonparametric bootstrap approach in four steps: 1) with the base pharmacokinetic model, 100 bootstrap replicates of the original data were generated by sampling with replacement; 2) ascertainment that each bootstrap data replicate was described by the basic structural model using the NONMEM objective function; 3) generalized additive modeling (GAM) applied to empiric Bayesian estimates for covariate selection at alpha = 0.05 and a frequency (f) cutoff value of 0.50; and 4) NONMEM population model building using covariates selected in the third step with alpha = 0.005. Performance of the population pharmacokinetic model was evaluated using 200 additional bootstrap replicates of the data by fitting the model obtained in step 4 to them. Parameters obtained were compared with those obtained in the model stability step, and improved prediction error, a measure of predictive accuracy as an index of internal validation, was computed. The reciprocal of serum creatinine (RSC; f = 0.73) and HIV (f = 0.70) were selected by GAM as predictors of clearance (Cl). The population pharmacokinetic model obtained without the determination of model stability included RSC as a predictor of Cl, but the final model from the model stability step included both HIV and RSC as predictors of Cl. Final population pharmacokinetic parameters were obtained with this model fitted to the original data; however, the 95% confidence interval on the HIV status regression coefficient included zero, indicating no significance. The mean parameter estimates obtained with the additional 200 bootstrap replicates of data were within 15% of those obtained with the final model at the regression stability step. Bootstrap resampling procedure is useful for evaluating the stability and performance of a population model by repeatedly fitting it to the bootstrap samples when there is no test data set.
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PMID:Stability and performance of a population pharmacokinetic model. 920 55


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