Biomedical subjects

Christine Armbruster

Publications and source records attributed to Christine Armbruster.

7 recordsLinked to original sources

PubMed2006

Neurosarcoidosis--a diagnostic pitfall with consequences.

Neurosarcoidosis is often a diagnostic dilemma, especially in the absence of other organ involvement. We report a 64-year-old patient who had suffered from paraplegia due to an intramedullar process since 1995. The presumptive diagnosis based on computed tomography was spinal cord infarction. Six years later, he complained about increasing paresthesia. Magnetic resonance imaging of the spinal cord showed nodular meningeal enhancement. Computed tomography of the thorax revealed mediastinal and hilar lymphadenopathy. Bronchoscopy under generalized anesthesia was performed. The differential cell count in bronchoalveolar lavage fluid showed 39% lymphocytes and a CD4(+)/CD8(+) ratio of 17.7. Histological examination of biopsy specimens from the hilar lymph nodes revealed non-necrotizing granulomas with epitheloid cells and Langerhans-type giant cells, consistent with the diagnosis of sarcoidosis. As a result of these findings, lumbar puncture was undertaken and a raised protein concentration and pleocytosis were found in the cerebrospinal fluid. The number of lymphocytes (9,250 lymphocytes/l) and a CD4(+)/CD8(+) ratio of 10.78 led to the diagnosis of neurosarcoidosis. Paralysis might have been prevented if the correct diagnosis of neurosarcoidosis had been established earlier in this patient.

Cerebrospinal Fluid Proteins↗

PubMed2006

Long-term multiple-dose pharmacokinetics of human monoclonal antibodies (MAbs) against human immunodeficiency virus type 1 envelope gp120 (MAb 2G12) and gp41 (MAbs 4E10 and 2F5).

While certain antibodies directed against the human immunodeficiency virus (HIV) envelope have the potential to suppress virus replication in vitro, the impact of neutralizing antibodies in vivo remains unclear. In a recent proof-of-concept study, the broadly neutralizing monoclonal antibodies 2G12, 4E10, and 2F5 exhibited inhibitory activities in vivo, as exemplified by a delay of the viral rebound following the interruption of antiretroviral therapy. Unexpectedly, the antiviral effect seen was most prominently due to 2G12 activity. To further investigate whether differential HIV-inhibitory activity was due to different pharmacokinetic properties of the antibodies, we performed a formal pharmacokinetic analysis with 14 patients. Repeated infusions at high dose levels were well tolerated by the patients and did not elicit an endogenous immune response against the monoclonal antibodies. The pharmacokinetic parameters of all three antibodies correlated with each other. Mean estimates were 0.047, 0.035, and 0.044 liter/kg for the central volume of distribution of 2G12, 4E10, and 2F5, respectively, and 0.0018, 0.0058, and 0.0077 liter/kg . day for the systemic clearance of 2G12, 4E10, and 2F5, respectively. Monoclonal antibody 2G12 had a significantly longer elimination half-life (21.8 +/- 7.2 days [P < 0.0001]) than monoclonal antibodies 4E10 (5.5 +/- 2.2 days) and 2F5 (4.3 +/- 1.1 days). The comprehensive pharmacokinetic data from this long-term multiple-dose phase II study were coherent with those from previous short-term phase I studies, as assessed by compartmental and noncompartmental techniques. The anti-HIV type 1 antibodies studied showed distribution and elimination kinetics similar to those seen for other human-like antibodies. Further studies examining tissue concentrations to explain the differential in vivo activity of the anti-gp120 antibody compared with those of the two anti-gp41 antibodies are warranted.

Adult↗

PubMed2004

Passive immunization with the anti-HIV-1 human monoclonal antibody (hMAb) 4E10 and the hMAb combination 4E10/2F5/2G12.

OBJECTIVES: To study the safety, immunogenicity and pharmacokinetics of the human monoclonal antibody (hMAb) 4E10 alone and in combination with the hMAbs 2F5 and 2G12 in HIV-1-infected persons. MATERIALS AND METHODS: Eight healthy volunteers with > or =350 CD4 cells/mm3 and < or =100 000 HIV-1 RNA copies/mL were enrolled, seven finished the study. A single 4E10 infusion was administered on day 0, followed by three doses of the hMAb combination 4E10/2F5/2G12 on days 7, 14 and 21 (total amount 8.5 g). Safety was assessed by physical examination, blood chemistry, complete blood cell count and recording of adverse events. 4E10, 2F5 and 2G12 plasma levels were determined before and at the end of each infusion and during the 7 week follow-up. RESULTS: No drug-related adverse events were observed throughout the study. The median plasma concentrations immediately after the first infusion were 371, 253 and 139 microg/mL for 4E10, 2F5 and 2G12. Multiple infusions resulted in maximum plasma concentrations of 407, 294 and 210 microg/mL for 4E10, 2F5, and 2G12, respectively. The median elimination half-lives (t1/2beta) were 6.6, 3.2 and 14.1 days for 4E10, 2F5 and 2G12. A low level antibody response against 2G12 was found in two patients. CONCLUSION: This Phase I trial showed that the hMAb 4E10 can be safely administered, both alone and in combination with 2F5 and 2G12 to HIV-1-infected patients.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Immunoglobulin G Fc(gamma) receptor expression on polymorphonuclear cells in bronchoalveolar lavage fluid of HIV-infected and HIV-seronegative patients with bacterial pneumonia.

This study was designed to test the hypothesis that impaired neutrophil function might contribute to the development of bacterial pneumonia in patients with HIV-infection. Numbers of inflammatory cells and immunoglobulin G Fcgamma receptor (IgG FcgammaR) I, II, III levels were investigated in bronchoalveolar lavage (BAL) fluid of HIV-seronegative and HIV-infected patients with bacterial pneumonia. The 99 patients were classified into three groups: I: HIV-seronegative and pneumonia (n = 40); II: HIV-infected and pneumonia (n = 19); III: HIV-seronegative with other pulmonary diseases than pneumonia (n = 40). The results of groups I and II, II and III, and I and III were compared. The percentage of alveolar macrophages was significantly lower (group II vs. III: p = 0.005, group I vs. III: p = 0.001), that of neutrophils increased significantly in patients with pneumonia (group II vs. III: p = 0.02, group I vs. III: p = 0.01). Lymphocytes differed only between groups I and III (p = 0.04). Although only the expression of FcgammaRI was significantly higher in HIV-seronegative pneumonia patients compared to those without pneumonia (p = 0.01), the mean expression of all three receptors was lower in the HIV-infected group, with that of FcgammaRI approaching statistical significance. This report provides first evidence that altered FcgammaR expression on BAL neutrophils might contribute to the increased susceptibility of HIV-infected patients to bacterial pneumonia.

Adult↗

PubMed2002

Antiviral activity of the neutralizing antibodies 2F5 and 2G12 in asymptomatic HIV-1-infected humans: a phase I evaluation.

BACKGROUND: The human monoclonal antibodies (MAbs) 2F5 and 2G12 were identified to be two of the most potent neutralizing antibodies against HIV-1. In a first human study they have been shown to be safe after repeated intravenous infusions to asymptomatic HIV-1-infected individuals. However, the antiviral effects of antibody treatment have not been fully analyzed in this first clinical trial. METHODS: The aim of the present study was to gain a preliminary insight into the antiviral effects of 2F5 and 2G12 in humans. For this purpose, plasma samples obtained from the previous phase I study were studied for RNA copy numbers by reverse transcriptase-polymerase chain reaction. As a measure for activation of complement levels of the major complement factor C3 were measured by enzyme-linked immunosorbent assay. Flow cytometry was used to study T-lymphocyte counts and the amount of infected peripheral blood mononuclear cells (PBMC) was determined by co-culture with uninfected donor PBMC. Virus escape from antibody neutralization was determined in vitro in a PBMC neutralization assay. RESULTS: Transient reduction in viral loads was observed in five of seven patients. Vigorous complement activation was observed directly after HIV-specific antibody infusions. The number of infective peripheral blood mononuclear cells was reduced in some patients whereas CD4+ T-lymphocyte counts and CD4+/CD8+ ratios were transiently increased in all patients. Virus escape occurred only against 2G12. CONCLUSIONS: Analysis of disease progression markers indicate that antibody therapy may have antiviral effects. These findings suggest that neutralizing antibodies should be further evaluated as an alternative therapeutic approach in HIV-1 disease.

Adult↗

PubMed2002

A phase I trial with two human monoclonal antibodies (hMAb 2F5, 2G12) against HIV-1.

OBJECTIVE: To study the safety, immunogenicity and pharmacokinetics of two intravenously administered human monoclonal antibodies (hMAb 2F5, 2G12) against HIV-1 in humans. DESIGN: Open label clinical phase I trial. SETTING: Primary institutional care. PATIENTS: Seven HIV-1-infected healthy volunteers with > or = 500 x 10(6)CD4 cells/l and < or = 10,000 HIV-1 RNA copies/ml, not treated with highly active antiretroviral therapy (HAART), entered and finished the study. INTERVENTIONS: and main outcome measures: Eight separate infusions of the hMAb were administered over a 4-week period (total dose 14 g). The safety was assessed by physical examination, blood chemistry, complete blood cell count and recording adverse events. 2F5 and 2G12 plasma levels were determined prior to and at the end of each infusion and during the follow-up period of 22 weeks. RESULTS: No clinical or laboratory abnormalities were observed throughout the study. The median distribution half-life (t(1/2 alpha)) of 2F5 and 2G12 was 1.02 (range, 0.77-1.47) days and 2.49 (range, 0.92-4.59) days, respectively. The elimination half-life (t(1/2 beta)) was calculated to be 7.94 (range, 3.46-8.31) days for 2F5 and 16.48 (range, 12.84-24.85) days for 2G12. The median plasma concentration immediately after the first infusion was 216 microg/ml (range, 158-409 microg/ml) for 2F5 and 238 microg/ml (range, 197-402 microg/ml) for 2G12. Multiple infusions resulted in maximum plasma concentrations of 374 microg/ml (range, 304-700 microg/ml) and 605 microg/ml (range, 479-897 microg/ml) for 2F5 and 2G12, respectively. CONCLUSIONS: This study showed that the hMAb 2F5 and 2G12 are safe and well tolerated by HIV-1-infected subjects.

Adult↗

PubMed2002

Novel treatments for recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis is a rare but often severe disease. Although benign in histology, epithelial proliferations may result in progressive hoarseness, stridor, obstruction of the airway and respiratory distress. The current standard of care is surgical therapy with a goal of complete removal or debulking of papillomas and preservation of normal structures. Frequent recurrences and the need for repeated surgical interventions make this treatment a frustrating experience for both the patient and the physician. Many adjuvant therapies have been investigated but no single treatment modality proved to be effective in eradicating recurrent respiratory papillomatosis. In contrast to HIV, cytomegalovirus and hepatitis B pharmaceutical research has been less successful with human papilloma virus vaccines for a variety of reasons. This review focuses on the current status of recurrent respiratory papillomatosis and on future directions of prevention and therapy.

Antiviral Agents↗