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Biomedical subjects

R Linde

Publications and source records attributed to R Linde.

At least 19 recordsLinked to original sources
PubMed2006

Need for therapeutic drug monitoring in HIV-1 infected children receiving efavirenz doses according to international guidelines.

BACKGROUND: International guidelines for the treatment of HIV-1 infected children recommend efavirenz plus nucleoside reverse transcriptase inhibitor combination therapy for first line therapy. Until now little is known about the steady state pharmacokinetics of efavirenz in children. METHODS: 11 HIV-1 infected children at the age of 4 to 10 years received efavirenz according to body weight adjusted dose recommendations at 10 -15 mg/kg body weight. All children were non nucleoside reverse transcriptase inhibitor (NNRTI) naive, 5/11 received efavirenz as first line therapy. Efavirenz plasma concentrations were assessed before daily dose and 1, 2, 4, 8, 24 h post-dose after medication by established HPLC. RESULTS: 7 of 11 children exhibited efavirenz plasma concentrations below targeted ranges. Mean (95% CI) minimum concentrations (C subsetmin) was 1293 ng/mL (range: 889 -1697) and maximum concentration (C subsetmax) was 5552 ng/mL (3951 - 7153) and the mean area under the time-concentration curve at steady state (AUCss) was 63608 ng*h/mL (44222 - 82989). The linear regression analysis of bodyweight adjusted efavirenz AUCss showed a close correlation between dose/bodyweight and plasma concentrations (r superset2 = 0.79). Efavirenz doses below 12.5 mg/kg lead to an AUC < 60000 ng*h/mL in 7 of 8 cases. Higher efavirenz doses exhibited an AUC within the recommended therapeutic range of 60000 - 120000 ng*h/mL (n = 3). CONCLUSIONS: The data show insufficient plasma concentrations for some children despite efavirenz dosing according to recommendations. Antiretroviral therapy needs to be carefully adjusted in children. Therapeutic drug monitoring is strongly recommended to meet efavirenz plasma levels within the therapeutic range.

Alkynes↗
PubMed2005

Effect of first line therapy including efavirenz and two nucleoside reverse transcriptase inhibitors in HIV-infected children.

OBJECTIVE: In an intent-to-treat study, reduction of viral load, increase in CD4 cell count, clinical benefit and adverse reactions were examined in HIV-infected children receiving first line therapy including efavirenz. METHODS: The data of 10 perinatally infected children (median age: 5.8 years) were evaluated during a treatment period of 24 months. Viral load and CD4 cell count were measured every 4 - 8 weeks. Pharmacokinetic evaluations of efavirenz were performed in all patients at study onset. Adverse reactions were reported after obtaining interval history and examination. RESULTS: At base line, median CD4 cell count was 378 cells/microl (21%) and median viral load was 350,000 copies/ml (5.5 log10 copies/ml). After 24 months of treatment, the median viral load reduction was > 3.5 log10 copies/ ml and HIV-1 RNA < 50 copies/ml was found in 8/10 children (80%). Median CD4 cell count increased to 721 cells/microl (24%) after 3 months and was maintained at a level of >1000 cells/microl (> 25%) after 24 months of treatment. Regarding efavirenz levels, C min. values ranged from 845 to 3550 ng/ml (median: 1845 ng/ml) and C max. values from 2380 to 24 200 ng/ ml (median: 3670 ng/ml). The most common adverse effect was a mild skin rash (4/10 children). CNS symptoms were recorded in one patient and no hyperlipidaemia was seen. CONCLUSION: First line therapy with efavirenz and two NRTIs was well tolerated by HIV-1 infected children and the reduction of viral load seems to be similar to single protease inhibitor-containing regimens.

Administration, Oral↗
PubMed2005

[Management of HIV-positive pregnancies -- results from a retrospective study].

OBJECTIVE: The management of HIV-positive pregnancies was investigated in conjunction to pre-, peri and postpartal complications and the HIV transmission rate. PATIENTS AND METHODS: Retrospective study of 88 HIV-positive patients who were delivered at the Dept. of Obstetrics and Gynaecology during 1.1.1997-31.12.2001. RESULTS: HIV-positive patients showed significantly more prepartal complications, compared to control group. Low CD4-cell count (< or = 200/microl) or high viral load (> 10 000 HIV-copies/ml) was not associated with increased risk for transmission relevant complications. The overall HIV-transmission rate was 3.4 % (3/89 newborns; with ART 2.5 % [2/85], without ART 33.3 % [1/3]). The transmission rate increased with complications during pregnancy (7.7 % [2/26] vs. 1.6 % [1/61]). Newborns delivered < or = 35 (th) week of gestation showed a transmission rate of 5.3 % compared to 2.9 % of newborns delivered after the 35 (th) week of gestation. 98 % of the patients were delivered by cesarean section (primary: n = 71, prior: n = 15), spontaneously: n = 2). 97 % of patients (85/88) were treated with antiretroviral therapy (ART). No differences were found in the postpartal complication rate of HIV-positive to -negative patients. None of the newborns was breast fed. CONCLUSIONS: Treatment of this risk-pregnancies in HIV experienced centers significantly reduces the risk of HIV transmission.

Female↗
PubMed2002

Effect of antiretroviral triple combinations including the protease inhibitor nelfinavir in heavily pretreated children with HIV-1 infection.

BACKGROUND: In this retrospective study the effect of antiretroviral triple therapy including the protease-inhibitor nelfinavir (NFV) on CD4-cells and viral load (VL) in heavily pretreated HIV-infected children was evaluated. PATIENTS AND METHODS: 20 children (<18 years) were included. Median duration of antiretroviral pretreatment was 27 months (range, 7 65), median initial VL was 4.7 log subset 10 (3.2 6.1) and median relative CD4-cells was 17.5% (3 33). Patients were put on combinations with NFV because of treatment failure (increasing VL), intolerance to prior therapy with PIs or adherence problems with prior indinavir. Viral load (RT-PCR, detection limit 50 copies/ml) and CD4-cells were measured every 4-8 weeks. RESULTS: Median viral load decreased 1.2 log(10) (-1.3 2.5), 0.9 log(10) (-0.8 - 2.5) and 0.4 log(10) (-0.5 - 3.0) after 12, 24 and 36 weeks. The VL of 2 patients was below the detection limit (50 copies/ml) after 24 weeks. The relative CD4-cell count increased from a median of 17.5% to 22%, 23% and 25% after 12, 24 and 36 weeks, respectively. Side effects of NFV were usually mild. WHO grade 1 or 2 diarrhea occurred in 70% and moderate elevations of triglycerides in 40% of the patients. At 48 weeks 18/20 patients had to be switched to other combinations due to virological failure. CONCLUSIONS: In children with intensive prior antiretroviral therapy combination therapy including NFV lead to a modest short-term reduction of the VL and increase in CD4-cells. However, the long-term antiretroviral effect was poor.

Adolescent↗
PubMed2001

CD95 (APO-1/Fas) expression on naive CD4(+) T cells increases with disease progression in HIV-infected children and adolescents: effect of highly active antiretroviral therapy (HAART).

We studied the expression of the CD95 receptor (APO-1/Fas) on peripheral blood T cell subpopulations in 37 HIV-1-infected children and adolescents stratified according to disease stage or antiretroviral treatment regimen and compared the results to values obtained in 12 healthy age-matched control subjects. CD95 expression on CD45RA(+) CD45RO(-)/CD62L(+) (resting/naive) and CD45RO(+) CD45RA(-) (primed/memory) CD4(+) and CD8(+) T cells was assessed quantitatively by four-color and three-color flow cytometry. CD4(+) T cells contained a population of predominantly CD95(-) resting/naive cells and a population of CD95(high) primed/memory cells, whereas CD8(+) T cells had a more uniform pattern of CD95 expression. The percentage of CD95(+) CD4(+) T cells increased with disease progression because of both an augmented median fluorescence intensity on resting/naïve cells and an increased percentage of CD95(high) cells. Patients with highly active antiretroviral combination therapy who maintained stable CD4 counts in the presence of elevated plasma viral load had nearly normal numbers of CD95(-) resting/naive CD4(+) T cells, whereas CD95 expression in the CD8(+) T cell subset was still elevated compared with control subjects. Low CD95 expression on resting/naive CD4(+) T cells may therefore indicate a low risk for disease progression in antiretrovirally treated and untreated patients.

Adolescent↗
PubMed2001

The GLBT Health Access Project: a state-funded effort to improve access to care.

The Gay, Lesbian, Bisexual, and Transgender (GLBT) Health Access Project is a unique public-private collaboration working to eliminate barriers to health care for the GLBT community, foster development of comprehensive, culturally appropriate health promotion policies and health care services for GLBT people and their families, and expand appropriate data collection on GLBT health. Funded by the Massachusetts Department of Public Health, the project developed community standards of practice for provision of quality health care services to GLBT clients. A health access training curriculum was developed and technical assistance was offered to health care providers implementing the standards, which cover personnel, clients' rights, intake and assessment, service delivery and planning, confidentiality, and community outreach and health promotion. Training participants (324 individuals from 89 agencies) reported positive though not statistically significant changes in attitude.

Community Health Planning↗
PubMed2000

Elevated plasma levels of 90K (Mac-2 BP) immunostimulatory glycoprotein in HIV-1-infected children.

90K is a secreted serum glycoprotein with immune stimulatory activity. In this study, 90K plasma levels were determined by an enzyme-linked immunosorbent assay in 18 HIV-1-infected children and 10 uninfected control children. 90K levels in HIV-1-infected children (median, 12.5 microg/ml) were higher than in HIV-1 uninfected control group (6.3 microg/ml; P < 0.05). 90K levels of HIV-1-infected children classified as stage B and C (median, 15.0 microg/ml and 22.7 microg/ml, respectively) were higher compared to children with stage A disease (median, 7.0 microg/ml; P < 0.05). A positive correlation (r = 0.5; P < 0.05) was found between 90K levels and HIV-1 RNA levels in 137 plasma samples of 18 HIV-1-infected children collected during a period of 1 year. No correlation was found between 90K levels and CD4 cell counts. These results suggest that 90K plasma levels may represent a novel marker of disease progression in HIV-1-infected children.

Adjuvants, Immunologic↗
PubMed1999

Preliminary experiences with triple therapy including nelfinavir and two reverse transcriptase inhibitors in previously untreated HIV-infected children.

OBJECTIVE: In an intent-to-treat study increase in CD4 cell count, reduction of viral load, clinical benefit and adverse reactions were examined in HIV-infected previously treatment-naive children taking triple therapy. METHODS: sixteen HIV-infected children in category A or B on antiretroviral triple therapy were followed-up for a period of 12 months. In group I eight patients received zidovudine, lamivudine and nelfinavir; in group II eight patients received stavudine, didanosine and nelfinavir. Viral load and CD4 cell count were measured every 4-8 weeks. Plasma nelfinavir levels were assessed once in all patients at baseline and monitored in patients with increasing viral load. RESULTS: No significant differences were observed between treatment groups in terms of CD4 cell counts and viral load. A median viral load reduction of 2.8 log10 (range, 1.4-4.2 log10) was achieved over a period of 12 months in both groups. Viral load < 500 copies/ml was found in 69% of patients and viral load < 50 copies/ml in 44% of patients after 12 months. Median CD4 cell count increased from 656 x 10(6) to 850 x 10(6) cells/l after 3 months and was maintained at 813 x 10(6) cells/l after 12 months of treatment. Main side-effects were diarrhoea, rash and hyperlipidaemia. Except for application problems, both regimens were well tolerated. Appropriate formula and individual counselling must be performed during the first weeks of treatment in order to achieve good compliance in paediatric patients. CONCLUSION: Triple antiretroviral therapy shows a stronger and more sustained reduction of viral load in HIV-infected children compared with studies combining two nucleoside analogues.

Anti-HIV Agents↗
PubMed1999

Early effects of antiretroviral combination therapy on activation, apoptosis and regeneration of T cells in HIV-1-infected children and adolescents.

OBJECTIVES: To assess the relationship between apoptosis, activation and regeneration of T cells, and viral replication in paediatric patients with HIV-1 infection during antiretroviral therapy (ART). DESIGN: In 15 HIV-1-positive children and adolescents sequential blood samples were obtained during 16 episodes of ART using combinations of nucleosidic HIV-1 reverse transcriptase (RT)-inhibitors and HIV-1 protease inhibitors or non-nucleosidic RT-inhibitors. METHODS: We assessed sensitivity of freshly isolated peripheral blood T cells towards spontaneous, anti-CD95- and anti-CD3-induced apoptosis and activation before and after 6-8 weeks of ART. Expression of CD95, CD45RA, CD45RO and CD62L on CD4 and CD8 T cells and of CD34 on mononuclear cells was studied by multiparameter flow cytometry before and after 10-12 weeks of ART. RESULTS: ART caused a significant increase in absolute lymphocyte and CD4 T cell counts (P < 0.03 and P < 0.02, respectively) and a decrease in both anti-CD95- and anti-CD3-induced apoptosis of CD4 and CD8 T cells to near normal levels even in patients without complete suppression of viral replication. A significant reduction in the percentage of CD95 (but not of CD95high) CD4 T cells was observed (P < 0.005). Resting/naive cells contributed significantly (P < 0.03) to the rise in CD4 T cells especially in infants and young children. CONCLUSIONS: Different mechanisms may contribute to early T cell reconstitution in HIV-1-infected children and adolescents during ART: decreased activation-induced apoptosis leading to increased survival of circulating primed/memory T cells; decreased activation-induced naive-to-memory shift increasing the frequency of circulating resting/naive T cells; increased input of haematopoietic progenitor cells from the bone marrow into the thymus and decreased intrathymic T cell death leading to an increased thymic output of naive T cells.

Adolescent↗
PubMed1999

Expression of CD69 on T-cells from HIV-1-infected children and adolescents increases with increasing viral load.

We evaluated the use of a whole-blood assay that measures spontaneous and activation-induced CD69 expression on peripheral blood T-cells in vitro for assessment of T-cell function in HIV-1-infected paediatric patients. Heparinized venous blood from 28 HIV-1 positive children and adolescents and 23 healthy controls was incubated for 4 h with or without 5 microg/ml phytohaemagglutinin (PHA). Thereafter, analysis of CD69 expression on CD4+ and CD8+ T-cells was done by flow cytometry; simultaneously we determined CD4+ T-cell counts and plasma HIV-1 viral load. Neither spontaneous nor PHA-induced CD69 expression differed significantly between HIV-1 positive patients and healthy controls. However, T-cells from HIV-1 positive patients with plasma HIV-1 viral load levels above 70x10(3) copies/ml showed a higher spontaneous CD69 expression than T-cells from patients with lower plasma viral load levels in different stages of the disease. Antiretroviral treatment in four patients reduced spontaneous CD69 expression in CD4+ T-cells and PHA-induced CD69 expression in CD4+ and CD8+ T-cells significantly after 8 weeks of therapy. Conclusion Spontaneous and activation-induced expression of the early (activation) antigen CD69 on peripheral blood T-cells does not distinguish HIV-1 positive patients from HIV-1 negative healthy controls and is not correlated with peripheral blood CD4+ T-cell counts. This test may not be a reliable marker for functional T-cell deficiency during early stages of HIV disease. Increased spontaneous as well as PHA-induced CD69 expression on T-cells from HIV-1-infected children and adolescents in vitro may rather reflect HIV-induced pre-activation of T-cells in vivo.

Adolescent↗
PubMed1999

The Kety-Schmidt technique for repeated measurements of global cerebral blood flow and metabolism in the conscious rat.

Cerebral activation will increase cerebral blood flow (CBF) and cerebral glucose uptake (CMRglc) more than it increases cerebral uptake of oxygen (CMR(O2)). To study this phenomenon, we present an application of the Kety-Schmidt technique that enables repetitive simultaneous determination of CBF, CMR(O2), CMRglc and CMRlac on awake, non-stressed animals. After constant intravenous infusion with 133Xenon, tracer infusion is terminated, and systemic arterial blood and cerebral venous blood are continuously withdrawn for 9 min. In this paper, we evaluate if the assumptions applied with the Kety-Schmidt technique are fulfilled with our application of the method. When measured twice in the same animal, the intra-individual variation for CBF, CMR(O2), and CMRglc were 10% (SD: 25%), 8% (SD: 25%), and 9% (SD: 28%), respectively. In the awake rat the values obtained for CBF, CMR(O2) and CMRglc were 106 mL [100 g](-1) min(-1), 374 micromole [100 g](-1) min(-1) and 66 micromole [100 g](-1) min(-1), respectively. The glucose taken up by the brain during wakefulness was fully accounted for by oxidation and cerebral lactate efflux. Anaesthesia with pentobarbital induced a uniform reduction of cerebral blood flow and metabolism by approximately 40%. During halothane anaesthesia CBF and CMRglc increased by approximately 50%, while CMR(O2) was unchanged.

Animals↗
PubMed1998

Activation-induced resetting of cerebral oxygen and glucose uptake in the rat.

In the clinical setting it has been shown that activation will increase cerebral glucose uptake in excess of cerebral oxygen uptake. To study this phenomenon further, this study presents an experimental setup that enables precise determination of the ratio between cerebral uptake of glucose and oxygen in the awake rat. Global CBF was measured by the Kety-Schmidt technique, and the ratio between cerebral uptake rates for oxygen, glucose, and lactate was calculated from cerebral arterial-venous differences. During baseline conditions, rats were kept in a closed box designed to minimize interference. During baseline conditions CBF was 1.08 +/- 0.25 mL x g(-1) x minute(-1), and the cerebral oxygen to glucose uptake ratio was 5.5. Activation was induced by opening the sheltering box for 6 minutes. Activation increased CBF to 1.81 mL x g(-1) x minute(-1). During activation cerebral glucose uptake increased disproportionately to cerebral oxygen uptake, and the cerebral oxygen to glucose uptake ratio was 4.2. The accumulated excess glucose uptake during 6 minutes of activation amounted to 2.4 micromol/g. Activation was terminated by closure of the sheltering box. In the postactivation period, the cerebral oxygen to glucose uptake ratio rose to a maximum of 6.4. This response is exactly opposite to the excess cerebral glucose uptake observed during activation.

Animals↗
PubMed1996

Is calcium accumulation post-injury an indicator of cell damage?

It is generally agreed that excessive intracellular calcium accumulation is the main culprit for nerve cell damage following brain injury. Many autoradiographic studies of the post-injury brain have demonstrated an accumulation of 45Ca2+ in regions exhibiting neuronal damage. We have recently observed, after cortical contusion trauma [10], that there was a discrepancy between the extent of cell damage and the extent of 45Ca2+ in autoradiograms; rather the distribution of 45Ca2+ followed that of serum proteins. In addition 45Ca2+ was also observed in white matter, which had no signs of damage. We tested the hypothesis that 45Ca2+ accumulation was coupled to the presence of protein by directly injecting albumin into the brain cortex. There was a highly significant correlation between the content of 45Ca2+ and of albumin as measured by ELISA. A similar pattern was found after a cortical freeze-lesion in the contralateral hemisphere. However, in the ipsilateral hemisphere where cell damage was observed, the relation broke down and calcium accumulated in excess. We conclude that calcium accumulation in the brain is not only the result of cell damage but also the presence of calcium-binding proteins, e.g. albumin.

Animals↗