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Biomedical subjects

R E Walker

Publications and source records attributed to R E Walker.

At least 37 records · Page 2Linked to original sources
PubMed1999

A multiple drug interaction study of stavudine with agents for opportunistic infections in human immunodeficiency virus-infected patients.

The effects of multiple opportunistic infection medications on stavudine pharmacokinetics were evaluated. Ten patients with CD4 counts of less than 200 cells/mm3 received stavudine (40 mg twice daily) in combination with one to three other drugs used to treat opportunistic infections. Serial blood samples for stavudine concentrations were collected after 1 week of therapy on each regimen and assayed for stavudine by using a validated high-pressure liquid chromatography method. Although the maximum concentration of drug in serum was significantly decreased when the drug was given in combination with three opportunistic infection medications, the area under the concentration-time curve did not significantly differ across various treatment regimens. Stavudine exposure was not significantly altered by multiple concomitant medications. Side effects were minor throughout the 3-month study period. The tolerability of stavudine, combined with its lack of drug interactions, makes it an attractive agent for use as part of a combination regimen.

AIDS-Related Opportunistic Infections↗
PubMed1999

Pharmacokinetics and safety of high-dose and extended-interval regimens of levofloxacin in human immunodeficiency virus-infected patients.

The pharmacokinetics of levofloxacin, administered in high doses and with extended dosing intervals, was studied in human immunodeficiency virus (HIV)-infected patients. Thirty patients received either 750 mg of the drug or a placebo once daily for 14 days, followed by 750 mg or 1,000 mg of the drug or a placebo three times weekly for an additional 14 days. Levofloxacin disposition was characterized by rapid oral absorption, with peak concentrations occurring approximately 1.5 h after dosing and elimination half-lives from 7.2 to 9.4 h. The overall incidence of any adverse effect was 70% (1,000 mg) to 95% (750 mg) for levofloxacin-treated patients and 71% for those taking the placebo. Levofloxacin pharmacokinetic parameters for HIV-infected patients were consistent with those observed in studies of healthy volunteers.

Administration, Oral↗
PubMed1999

Atovaquone suspension in HIV-infected volunteers: pharmacokinetics, pharmacodynamics, and TMP-SMX interaction study.

STUDY OBJECTIVE: To evaluate the pharmacokinetics and safety of atovaquone suspension in volunteers infected with the human immunodeficiency virus ((HIV). DESIGN: Open-label, nonrandomized study. SETTING: Two clinical research centers. PATIENTS: Twenty-two HIV-infected volunteers with a median CD4 cell count of 37 cells/mm3. INTERVENTIONS: Patients received atovaquone suspension fasting or fed for 2-week periods with crossover at dosages of 500 mg/day, and randomization to fasting or fed at dosages of 750 and 1000 mg/day. A subset of patients also received 750 mg twice/day with food, and a subset of those who received 1000 mg/day fasting also received 1000 mg with food. During a long-term dosing phase, a subset of subjects were evaluated for an interaction between atovaquone and trimethoprim-sulfamethoxazole (TMP-SMX). MEASUREMENTS AND MAIN RESULTS: Average steady-state atovaquone concentrations at 500 mg were 6.7 +/- 3.2 microg/ml fasted and 11.3 +/- 5.0 microg/ml with food; at 750 mg, 9.9 +/- 7.1 microg/ml fasted and 12.5 +/- 5.9 microg/ml with food; at 1000 mg, 9.7 +/- 4.3 microg/ml fasted and 13.6 +/- 5.0 microg/ml with food; and at 1500 mg, 21.1 +/- 5.0 microg/ml with food. Thus, plasma concentrations were not proportional to dose. Concomitant food ingestion resulted in a 1.3- to 1.7-fold increase in values. Average steady-state concentrations were less than 10 microg/ml in 21% and more than 15 microg/ml in 36% of patients at 1000 mg/day with food; at 750 mg twice/day, all five patients had levels above 15 microg/ml. Atovaquone suspension was well tolerated; diarrhea, nausea, fatigue, and rash were the most common adverse events. Concomitant administration of TMP-SMX did not change atovaquone concentrations and resulted in small decreases in concentrations of TMP (16%) and SMX (10%). CONCLUSION: Plasma concentrations are significantly higher when atovaquone suspension is administered with food compared with fasting. Total doses of 1500 mg/day are likely to achieve concentrations effective for prophylaxis of Pneumocystis carinii pneumonia.

AIDS-Related Opportunistic Infections↗
PubMed1998

Prediction of fracture risk by radiographic absorptiometry and quantitative ultrasound: a prospective study.

Recent developments in computer-assisted radiographic absorptiometry (RA) and quantitative ultrasound techniques (QUS) provide readily accessible and relatively inexpensive methods for assessing bone mineral status. However, few population-based studies have investigated the ability of RA and ultrasound to predict fracture risk prospectively. We explored the ability of RA and QUS to predict fracture risk among 560 postmenopausal women from the Hawaii Osteoporosis Study; average follow-up was 2.7 years. An incident vertebral fracture was defined as a decrease of more than 15% in vertebral heights on subsequent films. Self-reported nonspine fractures were verified by medical records. The prospective associations of vertebral fractures, nonspine fractures, and any (spine or nonspine) fractures with bone measurements were examined using logistic regression, adjusting for age. Both phalangeal bone mineral density (BMD) and metacarpal BMD, measured using RA, predicted future fracture risk. The age-adjusted odds ratios (corresponding to 1 SD decrease in BMD) for vertebral fractures, nonspine fractures, and any fractures were 3.41, 1.50, and 1.91, respectively, for phalangeal BMD, and 1.71, 1.49, 1.55, respectively for metacarpal BMD. Calcaneal broadband ultrasound attenuation (BUA) also showed significant association with fracture risk, with age-adjusted odds ratios of 1.50, 1.89, and 1.72 for vertebral fractures, nonspine fractures, and any fractures, respectively. We conclude that hand RA and calcaneal BUA are significant predictors of nonspine fracture, vertebral fracture, and overall fracture risk. The attractive features of these techniques, such as portability, relatively low cost, and ease of use, make them promising alternatives to conventional bone measurement techniques used for the assessment of fracture risk.

Absorptiometry, Photon↗
PubMed1998

Peripheral expansion of pre-existing mature T cells is an important means of CD4+ T-cell regeneration HIV-infected adults.

The CD4+ T-cell pool in HIV-infected patients is in a constant state of flux as CD4+ T cells are infected and destroyed by HIV and new cells take their place. To study T-cell survival, we adoptively transferred peripheral blood lymphocytes transduced with the neomycin phosphotransferase gene between syngeneic twin pairs discordant for HIV infection. A stable fraction of marked CD4+ T cells persisted in the circulation for four to eighteen weeks after transfer in all patients. After this time there was a precipitous decline in marked cells in three of the patients. At approximately six months, marked cells were in lymphoid tissues in proportions comparable to those found in peripheral blood. In two patients, the proportion of total signal for the transgene (found by PCR analysis) in the CD4/CD45RA+ T-cell population relative to the CD4/CD45RO+ population increased in the weeks after cell infusion. These findings indicate that genetically-marked CD4+ T cells persist in vivo for weeks to months and that the CD4+ T-cell pool in adults is maintained mostly by the division of mature T cells rather than by differentiation of prethymic stem cells. Thus, after elements of the T-cell repertoire are lost through HIV infection, they may be difficult to replace.

Adult↗
PubMed1998

Usefulness of optimized gadolinium-enhanced fast fluid-attenuated inversion recovery MR imaging in revealing lesions of the brain.

OBJECTIVE: The purpose of this study was to compare the contrast enhancement of lesions of the brain revealed by gadolinium-enhanced optimized fast fluid-attenuated inversion recovery (FLAIR) MR imaging with that of lesions on gadolinium-enhanced optimized T1-weighted spin-echo MR imaging. SUBJECTS AND METHODS: Using computer simulations, we optimized the fast FLAIR parameters (TR, TEeff, and inversion time) and the T1-weighted spin-echo parameters (TR and TE) to provide maximum difference in signal intensity between enhancing lesions of the brain and white matter. Seventy-six consecutive patients referred for single-dose gadolinium-enhanced MR imaging of the brain underwent both optimized techniques, which were matched for spatial resolution, bandwidth, and number of excitations. The gadolinium-enhanced fast FLAIR and T -weighted spin-echo MR images were evaluated independently by two observers for number and size of enhancing lesions and for the degree of gray-white matter differentiation. Contrast-to-noise ratios were measured for enhancing lesions 1.0 cm or larger in diameter using 8 x 8 pixel regions of interest in the enhancing lesions and normal white matter. RESULTS: The most revealing parameters for fast FLAIR MR imaging proved to be a TR of 1500 msec, an inversion time of 683 msec, and a TEeff of 16 msec. For T1-weighted spin-echo MR imaging, the optimized parameters were a TR of 550 msec and a TE of 16 msec. In 28 patients, we saw enhancing lesions of the brain with at least one MR imaging technique. More lesions were seen on the T1-weighted spin-echo sequence (n = 141) than on the fast FLAIR sequence (n = 94) (p < .03). Gray-white matter differentiation was significantly better on the fast FLAIR sequence (p < .001). Contrast-to-noise ratios of enhancing lesions were greater on the T1-weighted spin-echo sequence (p < .001). CONCLUSION: In this study, optimized gadolinium-enhanced conventional T1-weighted spin-echo MR imaging proved superior to gadolinium-enhanced fast FLAIR MR imaging in revealing lesions of the brain.

Adult↗
PubMed1997

Phalangeal bone density and hip fracture risk.

OBJECTIVE: To assess the long-term predictive usefulness of radiographic absorptiometry measurements of phalangeal bone density for hip fracture risk. METHODS: Participants were members of the First National Health and Nutrition Examination Survey Epidemiologic Follow Up Study cohort. Subjects were followed up for a maximum of 16 years. The First National Health and Nutrition Examination Survey data were obtained from a nationally representative sample of non-institutionalized civilians. A cohort of 3481 white and black subjects (1559 white women) aged 45 through 74 years at baseline (1971-1975) were observed through 1987. Ninety-eight percent of the original cohort completed the study. Hospital records and death certificates were used to identify a total of 72 hip fracture cases. Phalangeal bone density at baseline was measured using photodensitometry (PD), and later reanalyzed by radiographic absorptiometry (RA), a newer, more sophisticated technique. RESULTS: Results were evaluated to determine the relative risk for hip fracture per 1-SD decrease in bone density, after controlling for age at baseline, race, gender, weight, and previous fractures. Both RA and PD measurements showed a significant inverse relationship to hip fracture risk, with RA density measurements showing a slightly higher adjusted relative risk per 1-SD density decrease than PD measurements. For RA bone density, the relative risk for all subjects was 1.81 (95% confidence interval, 1.34-2.44) compared with 1.57 (95% confidence interval, 1.19-2.07) for PD bone density after adjusting for age at baseline, race, gender, weight, and previous fractures. Results for white women were essentially the same as those for all subjects for RA bone density and PD bone density. CONCLUSIONS: Phalangeal bone density determined from standard hand x-ray films is a significant predictor of future hip fracture risk. Availability of a valid method to assess fracture risk using conventional radiographs will expand the ability to identify individuals with osteoporosis.

Absorptiometry, Photon↗
PubMed1997

Development of antibodies to fetal calf serum with arthus-like reactions in human immunodeficiency virus-infected patients given syngeneic lymphocyte infusions.

In an attempt to restore immune competence to 12 human immunodeficiency virus-1 (HIV-1)-infected patients, lymphocytes from their HIV-1-uninfected identical twin siblings were cultured in medium supplemented with 5% fetal calf serum (FCS), anti-CD3 antibody, and interleukin-2 (100 IU/mL) for 10 days and then infused into the patients. After multiple infusions, at 6- to 8-week intervals, half of the patients developed arthus-like reactions within 4 to 12 hours of infusion consisting of fever > 39 degrees C, hypotension, rigors, arthralgias, myalgias, headache, and/or malaise. Preinfusion and postinfusion serum samples were evaluated for the presence of antibodies to FCS using double immunodiffusion. All preinfusion serum samples were negative by this method while 8 of the 12 patients developed antibodies to a single component of FCS after two or more infusions of lymphocytes cultured in FCS-supplemented medium. Prick skin testing to standardized beef extract was negative in all patients. There was a correlation between initial CD4 level and the development of antibodies to FCS (median initial CD4 count in FCS antibody positive patients = 362.0/microL v median initial CD4 count of nonresponders = 135.0/microL). There was no correlation with response to recall antigens in delayed-type hypersensitivity testing. We conclude that selected patients were sensitized to a single component of FCS carried on donor lymphocytes, despite thorough washing of the cells before infusion. The development of antibodies to FCS indicates that immune complex formation could have occurred after the cell infusions, resulting in the arthus-like reactions. These observations suggest that the therapeutic use of human lymphocytes cultured in FCS may expose the recipient to immunogenic substances with possible clinical sequelae.

Animals↗
PubMed1997

HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies.

Changes in CD4+ T-cell surface marker phenotype and antigen receptor (TCR) repertoire were examined during the course of HIV infection and following therapy. A preferential decline in naive CD4+ T cells was noted as disease progressed. Following protease inhibitor therapy, naive CD4+ T cells increased only if they were present before initiation of therapy. Disruptions of the CD4+ TCR repertoire were most prevalent in patients with the lowest CD4+ T-cell counts. Antiviral or IL-12 therapy-induced increases in CD4+ T-cell counts led to only minor changes in previously disrupted repertoires. Thus, CD4+ T-cell death mediated by HIV-1 infection may result in a preferential decline in the number of naive CD4+ T cells and disruptions of the CD4+ T-cell repertoire that are not immediately corrected by antiviral or immune-based therapies.

CD4-Positive T-Lymphocytes↗
PubMed1997

Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons.

The safety and efficacy were assessed of 5-day cycles of subcutaneous (sc) interleukin-2 (IL-2) every 8 weeks in human immunodeficiency virus type 1-infected outpatients with >200 CD4 cells/mm3. Immunologic, virologic, and toxicity parameters were measured in 18 patients receiving standard antiretrovirals plus 5-day courses of sc IL-2 (3-18 MIU/day) every 2 months. Systemic toxicities established the maximally tolerated dose (MTD) of IL-2 as 15 MIU/day. CD4 cell responses appeared to correlate directly with baseline CD4 cell counts, with several patients experiencing a dramatic rise after 3 cycles. Virus load increased only transiently in the peri-injection period. It was concluded that serial cycles of outpatient sc IL-2 can be administered safely, with an MTD of 15 MIU/day. Patients with higher baseline counts appear to have a greater CD4 cell response to sc IL-2 therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Single-dose pharmacokinetics of thalidomide in human immunodeficiency virus-infected patients.

The pharmacokinetics of thalidomide in nine human immunodeficiency virus-infected patients were studied. Single doses of thalidomide were well absorbed, with mean peak concentrations (+/- standard deviations) of 1.17 +/- 0.21 and 3.47 +/- 1.14 microg/ml in the 100- and 300-mg dosing groups, respectively, and the mean elimination half-life was approximately 6 h. Adverse effects were mild, with drowsiness being reported for seven of nine patients.

Adult↗
PubMed1997

Clarithromycin lowers plasma zidovudine levels in persons with human immunodeficiency virus infection.

The use of antiretroviral agents and drugs for the treatment and prophylaxis of opportunistic infections has lengthened the survival of persons with AIDS. In the era of multidrug therapy, drug interactions are important considerations in designing effective and tolerable regimens. Clarithromycin has had a significant impact on the treatment of disseminated Mycobacterium avium complex infection, and zidovudine is the best-studied and one of the most widely used antiretroviral agents in this population. We conducted a study to determine the maximally tolerated dose of clarithromycin and the pharmacokinetics of clarithromycin and zidovudine individually and in combination. Mixing studies were conducted to simulate potential interaction in the gastric environment. The simultaneous administration of zidovudine and clarithromycin had little impact on the pharmacokinetics of clarithromycin or of its major metabolite. However, coadministration of zidovudine and clarithromycin at three doses (500 mg orally [p.o.] twice daily [b.i.d.], 1,000 mg p.o. b.i.d., and 2,000 mg p.o. b.i.d.) reduced the maximum concentration of zidovudine by 41% (P < 0.005) and the area under the concentration-time curve from 0 to 4 h for zidovudine by 25% (P < 0.05) and increased the time to maximum concentration of zidovudine by 84% (P < 0.05), compared with zidovudine administered alone. Mixing studies did not detect the formation of insoluble complexes due to chelation, suggesting that the decrease in zidovudine concentrations results from some other mechanism. Simultaneous administration of zidovudine and clarithromycin appears to decrease the levels of zidovudine in serum, and it may be advisable that these drugs not be given at the same time. Drug interactions should be carefully evaluated in persons with advanced human immunodeficiency virus infection who are receiving multiple pharmacologic agents.

Adult↗
PubMed1996

Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus.

BACKGROUND: Interleukin-2 is a cytokine that regulates the proliferation and differentiation of lymphocytes. In preliminary studies, intermittent infusions of interleukin-2 led to increases in CD4 counts in patients with human immunodeficiency virus (HIV) infection and more than 200 CD4 cells per cubic millimeter. We conducted a controlled study to evaluate the long-term effects of such therapy on both CD4 counts and the viral burden. METHODS: Sixty HIV-infected patients with base-line CD4 counts above 200 cells per cubic millimeter were randomly assigned to receive either interleukin-2 plus antiretroviral therapy (31 patients, 1 of whom was lost to follow-up) or antiretroviral therapy alone (29 patients). Interleukin-2 was administered every two months for six cycles of five days each, starting at a dosage of 18 million i.u. per day. Safety and immunologic and virologic measures were monitored monthly until four months after the last treatment cycle. RESULTS: In patients treated with interleukin-2, the mean (+/-SE) CD4 count increased from 428 +/- 25 cells per cubic millimeter at base line to 916 +/- 128 at month 12, whereas in the control group, the mean CD4 count decreased from 406 +/- 29 cells per cubic millimeter to 349 +/- 41 (P < 0.001). There were no significant differences between the groups in serial measurements of the plasma HIV RNA or p24 antigen concentration during the 12 months of treatment. Constitutional symptoms (fever, malaise, and fatigue) and asymptomatic hyperbilirubinemia were the chief dose-limiting toxic effects of interleukin-2 therapy. CONCLUSIONS: In patients with HIV infection and base-line CD4 counts above 200 cells per cubic millimeter, intermittent infusions of interleukin-2 produced substantial and sustained increases in CD4 counts with no associated increase in plasma HIV RNA levels.

AIDS-Related Opportunistic Infections↗