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PubMed1997

Fractal analysis of lung alveoli during the acute phase vs. repair phase of an adenoviral infection in canines.

Acute viral respiratory infections are commonly associated with alterations in lung growth. Recently, fractal techniques have been demonstrated to show changes in alveolar perimeter after canine adenovirus type 2 (CAV2) infection in a beagle puppy model. In the present study, we investigated whether the fractal dimension (Df) of the alveolar perimeter was changed in the acute phase (2-3 weeks after inoculation, 131d CAV2 group) or during the recovery phase (approximately 22 weeks after inoculation, 235d CAV2 group) after a single bout of CAV2. There were sham CAV2 groups, 130d and 238d controls, corresponding to the CAV2 groups. The Df of alveolar perimeter length was significantly increased in the 235d CAV2 puppies compared to all of the other beagle puppy groups. On the other hand, the fractal dimensions for alveolar perimeter length for the other beagle puppy groups were very similar. In a related human study of patients (age range of 25 h to 19 y, N = 11), who died of non-respiratory causes, showed no consistent change in Df of alveolar perimeter length with normal lung growth and development. We conclude that fractal analysis of alveolar perimeter length can be used as an index of permanent lung injury after insult to the growing lungs.

Acute Disease↗
PubMed1998

[Advanced sleep phase syndrome (ASPS) and delayed sleep phase syndrome (DSPS)].

Circadian rhythm sleep disorders which may result from dysfunction of biological clock have recently been noticed and the number of patients suffering from these types of sleep disorders have been increased. In this article, clinical features, pathophysiological aspects, diagnoses and treatments for advanced sleep phase syndrome (ASPS) and delayed sleep phase syndrome (DSPS) are described. Although the pathophysiology or the etiology of ASPS and DSPS have not definitely been elucidated, the evidence that the chronobiological treatments sometimes improve patients with these disorders confirms the possibility that circadian rhythm sleep disorders are caused by dysfunction of biological clock. Further studies based on chronobiology or molecular biology are necessary to clarify the pathophysiology or the etiology of ASPS and DSPS and to develop the treatments against these circadian rhythm sleep disorders.

Animals↗
PubMed1998

[MRI phase contrast flow measurement of portal vein: influence and compensation of respiratory motion and propriety of phase correction using background].

The purposes of this study were to (1) determine which condition, breath holding (BH) or quiet breathing (QB), is better for phase contrast (PC) measurement of the portal flow (PF); (2) assess the usefulness of respiratory compensation (RC), a technique that diminishes motion artifacts due to breathing, on PC flow measurement; and (3) evaluate the propriety of phase correction (PhC) using background for PC flow measurement. For purposes (1) and (2) respiratory simulation phantom (RSP) was measured, and PF measurements were performed in 6 healthy subjects (HS) and 53 patients. Thirty of the patients had liver cirrhosis (LC) and 23 did not. For purpose (3), flow measurements were carried out in the phantom and 6 HS. (1) In 6 HS, intra-subjective coefficients of variation (CV) were smaller under QB than under BH (p < 0.05). And PF in patients with LC was less than in those not under QB (p < 0.01). This difference was not statistically significant under BH. (2) In the RSP study PC flow measurement with high sort RC showed good reliability. (3) Intraobserver variation was smaller without PhC than with PhC (p < 0.05) in the HS study. It may be more useful to perform portal flow measurements under QB with RC and without PhC than with PhC or under BH.

Adult↗
PubMed1995

Influence of renal function on the steady-state pharmacokinetics of the antiarrhythmic propafenone and its phase I and phase II metabolites.

The aim of this study was to investigate the disposition of propafenone and its Phase I and II metabolites in relation to kidney function under steady-state conditions. The mechanism of the renal handling of propafenone glucuronides (filtration, secretion) was also examined. Racemic (R/S) propafenone was administered to 7 young volunteers, to 5 older patients with a normal glomerular filtration rate and to 4 patients with chronic renal failure. No difference was found in the plasma concentrations of propafenone and 5-hydroxypropafenone between the three groups. The propafenone glucuronide (PPFG) concentration was elevated in the older compared to the younger subjects (S-PPFG: 544 vs. 222 nmol.ml-1.mol-1; R-PPFG: 576 vs. 304 nmol.ml-1.mol-1). Although Glomerular filtration rate did not differ, the renal clearance of propafenone glucuronides was reduced in the former group, which could be attributed to their impaired renal secretion. A dramatic increase in propafenone glucuronide concentration was observed in the patients with renal failure (S-PPFG: 2783 nmol.ml-1.mol-1; R-PPFG: 7340 nmol.ml-1.mol-1). In summary, the disposition of propafenone and of its active metabolite 5-hydroxypropafenone was not affected by kidney dysfunction, indicating that no dose adjustment is necessary in patients with renal failure. The accumulation of drug glucuronides in older patients with apparently normal kidney function should be taken into account as a possible factor modifying drug therapy.

Aged↗
PubMed2004

A phase I/II trial of oxidized autologous tumor vaccines during the "watch and wait" phase of chronic lymphocytic leukemia.

Based on their activity in patients with advanced stage chronic lymphocytic leukemia (CLL), a phase I/II study was designed to evaluate the feasibility, safety, and efficacy of autologous vaccines made from oxidized tumor cells in patients with earlier stage CLL, and to determine an optimal schedule of injections. Eighteen patients (at risk for disease progression and with white blood cell counts between 15 and 100 x 10(6) cells/ml) were injected intramuscularly with 10 ml of oxidized autologous blood (composed mainly of CLL cells) either 12 times over 6 weeks (group 1), 12 times over 16 days (group 2), or 4 times over 6 weeks (group 3). Fourteen out of eighteen patients had Rai stage 0-II disease, while 4/18 had stage III-IV disease but did not require conventional treatment. Partial clinical responses, associated with enhanced anti-tumor T cell activity in vitro, were observed in 5/18 patients of whom three were in group 2. Stable disease was observed in six patients while disease progression appeared not to be affected in the remaining patients. Toxicity was minimal. Vaccination with oxidized autologous tumor cells appears worthy of further investigation and may be a potential alternative to a "watch and wait" strategy for selected CLL patients.

Adult↗
PubMed1995

Increased serum alpha 1-antichymotrypsin in patients with probable Alzheimer's disease: an acute phase reactant without the peripheral acute phase response.

Serum levels of alpha 1-antichymotrypsin (alpha 1-ACT) were measured in patients with early and late onset Alzheimer's disease (e-AD, 1-AD), patients with vascular dementia (VD) and healthy elderly. Patients with 1-AD were divided into two groups, one had normal alpha 1-ACT values and one had increased serum levels of alpha 1-ACT. Other acute phase proteins were also measured. The serum levels of alpha 2-macroglobulin (alpha 2-MG), alpha 1-antitrypsin (alpha 1-AT), ceruloplasmin (CER), transferrin (TRSF) and alpha 1-acid glycoprotein (alpha 1-ac.GL) were within the normal range. The C reactive protein (CRP) was occasionally detectable at low concentrations in e-AD, in both groups of 1-AD patients and in VD patients. Low serum concentrations of interleukin-6 (IL-6) were found in a higher proportion of 1-AD than in patients with e-AD or VD. These results indicated that increased levels of alpha 1-ACT along with occasional detection of IL-6 might be peripheral markers of the 'acute reaction' in the brain.

Acute-Phase Proteins↗
PubMedDate not supplied

Rapid pulmonary expression of acute-phase reactants after local lipopolysaccharide exposure in mice is followed by an interleukin-6 mediated systemic acute-phase response.

This study investigated local and systemic innate immune responses in lipopolysaccharide (LPS)-induced lung inflammation in mice. Intratracheal LPS exposure resulted in increased pulmonary mRNA expression for acute-phase reactants (APRs) alpha(1)-antitrypsin (alpha(1)-AT), alpha(1)-acid glycoprotein (AGP), and LPS-binding protein (LBP) from 4 hours post exposure. Although pulmonary serum amyloid P component (SAP) mRNA was not increased, systemic levels of SAP, AGP, and LBP were elevated from 24 hours post exposure. Systemic APRs increase was associated with hepatic mRNA expression. As in vivo neutralization of interleukin (IL)-6, but not tumor necrosis factor (TNF)-alpha, fully ablated hepatic APR mRNA expression, IL-6 may act as signaling molecule between lung and liver. In conclusion, pulmonary LPS exposure induced rapid APR expression in lung, which precedes IL-6-mediated systemic elevation of APRs associated with hepatic APRs expression.

Acute-Phase Proteins↗
PubMed2002

A phase II study of topotecan in non-Hodgkin's lymphoma: an Ohio State University phase II research consortium study.

PURPOSE: This multicenter phase II trial evaluated the efficacy and toxicity of the topoisomerase I inhibitor topotecan (TPT, 9-dimethylaminomethyl-10-hydroxycamptothecin) in patients with refractory or relapsing non-Hodgkin's lymphoma. PATIENTS AND METHODS: Thirty-two patients with previously treated non-Hodgkin's lymphoma were accrued in this study from June 1992 to June 1997. Patients were eligible if they had measurable disease and had received two or less chemotherapy treatments for indolent lymphoma or no more than one treatment for aggressive lymphoma. Nineteen patients with aggressive lymphoma including seven with transformed indolent disease and 11 patients with indolent disease were treated. Two additional patients had both indolent and aggressive lymphoma in the bone marrow and lymph nodes at entrance into the study. Topotecan was administered as a 30-min infusion at a dose of 1.25 mg/m2 for five days and repeated at three week intervals. RESULTS: Thirty-two patients were evaluable for toxicity and 29 patients were evaluable for response. There were five objective responses including two complete remissions and three partial remissions (17%; CI 4-30%). Four of the five responders had aggressive disease and had been responsive to prior chemotherapy. The duration of remissions were short, lasting a median of 2 months (range 2-52 months). The major toxicity seen was myelosuppression with 28 of the 32 patients having grade three or greater granulocytopenia. CONCLUSION: Topotecan given as a five day 30 min infusion at a dose of 1.25 mg/m2 has modest activity in previously treated non-Hodgkin's lymphoma as compared to other active agents.

Adult↗
PubMed2001

Bridging phase 2 and phase 3 pneumococcal immunologic data for future combination vaccines.

Pneumococcal conjugate vaccines (PncCs) will be introduced into childhood vaccination programs now that the first PncC has been licensed for use. The next generation of PncCs and possible combination vaccines containing PncC will most probably be approved on the basis of phase 2 immunogenicity and safety data. PncCs are combination vaccines that include, at present, 7-11 components. Immune response to different components may vary. Furthermore, there seem to be population-based differences in immune response. Whether these differences are due to the other vaccines that are given simultaneously or due to the genetic background remains to be seen. Immune response can be evaluated by determining both the quantity and the quality of antibodies after vaccination. However, data are still missing on the minimal protective immune response and serologic correlates or surrogates of protection.

Antibodies, Bacterial↗
PubMed1998

Induction and modulation of acute-phase response by protein malnutrition in rats: comparative effect of systemic and localized inflammation on interleukin-6 and acute-phase protein synthesis.

The acute-phase protein (APP) response is regulated by cytokines such as interleukin-6 (IL-6), interleukin-1 (IL-1) and tumor necrosis factor (TNF), but may also be influenced by malnutrition. The aims of this study were as follows: 1) to determine in rats the effect of a protein-deficient diet on IL-6 mRNA expression in intestine, liver and peripheral blood mononuclear cells (PBMC), and on alpha-1 acid glycoprotein (AGP) and alpha-2 macroglobulin (A2M) serum levels and hepatic mRNA expression; 2) to compare, in protein-deficient rats, the IL-6 and APP responses after a turpentine (TO)- or a lipopolysaccharide (LPS)-induced inflammation; and 3) to determine the effect of a protein malnutrition on IL-6 mRNA expression in rat PBMC treated ex vivo with LPS. Interleukin-6 mRNA was present in intestine and PBMC but not in the liver of malnourished rats, and was absent in any tissue or cells of controls. A2M was present in the serum from malnourished rats but not after refeeding. AGP mRNA expression was not influenced by protein malnutrition. In malnourished rats, IL-6 serum level peaked later than in controls after TO and LPS treatment. In malnourished TO-treated rats, A2M mRNA increased earlier than in controls and remained detectable later than in controls. AGP mRNA expression after TO was not influenced by protein malnutrition. In PBMC of malnourished rats, LPS-induced IL-6 mRNA expression occurred earlier and lasted longer than in controls. Our results indicate that protein malnutrition by itself induces IL-6 and A2M expression, and that it modulates the APP response to inflammation.

Acute-Phase Proteins↗
PubMed1999

Nursing, morality, and emotions: phase I and phase II clinical trials and patients with cancer.

This article reflects three nurses' views of the moral dimensions of their work in caring for patients receiving phases I and II of cancer clinical trials in a dedicated cancer clinical trials unit (CCTU). The nurses took part in a semistructured, tape-recorded, group interview in which they talked about any aspect of their work that they felt demonstrated its ethical or moral dimensions. The nurses were not employed as research nurses, but had chosen to specialize in cancer and palliative care in a CCTU environment. Three key themes emerged from the interview: being valued and moral distress; caring in a climate of scientific research; and care, cure, and consequences for moral reasoning. Working in an environment suffused with moral conflicts can be painful and damaging for the professionals involved. It would appear that if nurses are to function effectively, they need to be proactive in promoting an exploration of the role that emotions play in moral decision making and in examining the contribution of emotions to what they care about and why. A commitment to a shared understanding and valuing of divergent ethical reasoning in and across professional cultures of care and research paradigms also appears to be necessary. The terms "ethics" and "morals" are used interchangeably throughout this article.

Attitude of Health Personnel↗
PubMed2003

Phase II study of oral vinorelbine in first-line advanced breast cancer chemotherapy.

PURPOSE: A phase II trial was performed to evaluate the efficacy, tolerance, and pharmacokinetic profiles of oral vinorelbine (Navelbine). Oral Navelbine (NVB; Pierre Fabre Médicament, Boulogne, France) was given as first-line chemotherapy for locally advanced or metastatic breast carcinoma (ABC). PATIENTS AND METHODS: Sixty-four patients were entered to receive oral NVB on a weekly basis for a total of 8 weeks unless progression or toxicity occurred. Oral NVB was given at 60 mg/m(2) weekly for the first three administrations and was increased to 80 mg/m(2) for the subsequent administrations if there was no grade 4 neutropenia or no more than one episode of grade 3 neutropenia. Patients with objective response or stable disease continued treatment up to a total of 12 weeks or more. RESULTS: Fifty-eight evaluable patients were included in our study. Four patients (6.9%) had complete responses, and 14 (24.1%) had partial responses, for an overall response rate of 31% (95% CI, 19% to 43%). Median progression-free survival was 17.4 weeks. Median overall survival is not yet reached. There were no treatment-related deaths. The main toxicity was neutropenia: grade 4 in 17.2% of the patients, and 1.8% of administrations and associated clinical serious events in 4 patients (6.2%). Grade 3 and 4 nausea and/or vomiting were noted in 3.1% and 4.6% of the patients, respectively. Only one patient developed grade 3 neuroconstipation. An analysis of Quality of Life Questionnaire C30 forms revealed no significant alteration between baseline and weeks 8 and 16 in global quality of life. CONCLUSION: Oral NVB at this schedule is an effective and well-tolerated agent in the treatment of ABC and offers a promising alternative to the intravenous route. Combination studies are ongoing.

Administration, Oral↗
PubMed1995

Effect of acute immunoneutralization of inhibin in ewes during the late luteal phase of the oestrous cycle on ovarian hormone secretion and follicular development during the subsequent follicular phase.

Ewes with ovarian autotransplants received either inhibin antiserum (10 ml i.v.; n = 6) or sheep serum (10 ml i.v.; n = 5) on day 10 of the luteal phase with additional daily injections (1 ml i.v.) from 48 h after the initial injection until the end of blood sampling, 9 days later. Luteal regression was induced by injection of prostaglandin F2 alpha (PGF2 alpha) 4.2 days after the initial plasma injection. Jugular and ovarian venous blood samples were taken every 4 h over the experimental period, and more frequent samples (every 10-15 min for 2-3 h) were taken to examine pulsatile secretory responses from the ovary to GnRH-induced (150 ng i.m. 1 and 4 days after initial treatment) or endogenous LH pulses (24 and 48 h after injection of PGF2 alpha). Plasma FSH concentrations, ovarian steroid secretion and ovarian follicular development were measured. Immunization against inhibin resulted in a two- to threefold increase (P < 0.001) in plasma FSH concentrations, which remained higher than controls until injection of PGF2 alpha. Within 24 h of immunization, there was an increase in the number of small ovarian follicles (P < 0.01) and by 4 days after treatment, immunized ewes had four or five (P < 0.01) large ovarian follicles and, despite little change in the basal steroid secretion, a four- to sixfold increase (P < 0.05) in the amplitude of the steroidogenic response to a GnRH-induced LH pulse.(ABSTRACT TRUNCATED AT 250 WORDS)

Androstenedione↗
PubMed1999

Docetaxel (Taxotere) and gemcitabine phase I and early phase II studies: results to date and an overview of ongoing studies.

Given their proven efficacy and different mechanisms of action, there exists a clear rationale for the combination of docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) and gemcitabine. In phase I studies, the combined use of these two new drugs at close to their recommended single-agent doses has proven feasible, active, and well tolerated. The gemcitabine/docetaxel combination, administered on days 1 and 8 of a 3-week cycle, may prove useful in many solid tumors, including those of the lung. In NSCLC, this use may extend from the setting of advanced disease to the adjuvant and neoadjuvant settings.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

[Role of gemcitabine in the treatment of advanced non-small cell lung cancer: review of the main phase II and phase III trials].

Marked advances in the treatment of non-small cell lung cancer (NSCLC) have been made thanks to new agents. Among these agents, gemcitabine appears to be a major compound in advanced stage NSCLC chemotherapy. To start with, several phase III trials (conducted in Europe and in the USA) studied the gemcitabine/cisplatin combination (GC): US study protocois compared GC to cisplatin alone, to the standard treatment (etoposide/cisplatin) or to platinum/taxane doublets; in these studies, as a result of treatment with GC, a higher survival rate was observed. A study conducted in Italy, which is undergoing analysis, observes GC versus paclitaxel/carboplatin versus cisplatin/vinorelbine. In addition, in newer clinical protocols, it was observed that gemcitabine combined with taxanes or with vinorelbine demonstrated efficacy at least equal to that of combinations with platinum analogs. Newer agents acting on epithelial growth factor are also undergoing evaluation.

Antimetabolites, Antineoplastic↗
PubMed1997

Acute phase proteins in salmonids: evolutionary analyses and acute phase response.

Inflammation induces dramatic changes in the biosynthetic profile of the liver, leading to increased serum concentrations of positive acute phase (AP) proteins and decreased concentrations of negative AP proteins. Serum amyloid A (SAA) and the pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP) are major AP proteins: their serum levels can rise by 1000-fold, indicating that they play a critical role in defense and/or the restoration of homeostasis. We have cloned SAA and a SAP-like pentraxin from salmonid fish species. The salmonid SAA shares approximately 70% amino acid identity with mammalian AP SAA. When salmonids are challenged with an AP stimulus, i.e., Aeromonas salmonicida, SAA responds dramatically as a major AP reactant. The salmonid pentraxin shows approximately 40% amino acid identity to both mammalian SAP and CRP. Evolutionary analysis suggests the presence of only a single such protein in teleosts and lower animal species. Surprisingly, the salmonid pentraxin behaves as a negative AP reactant, reminiscent of the SAP-like Syrian hamster female protein, in that hepatic mRNA concentrations decline to 50% of prestimulus levels. This study reinforces the hypothesis that SAA induction is an essential and universal feature of the vertebrate AP response and that it represents part of an ancient host defense system. Conversely, the species-dependent heterogeneity of pentraxin expression during the vertebrate AP response supports the possibility that its most important ancestral (and perhaps present) function is not related to its AP behavior.

Acute-Phase Proteins↗
PubMed1997

[Tumor necrosis factor-alpha--phase I and phase II clinical trials].

Not fully successful therapy of carcinomas makes us search for new methods of antitumor treatment. Beside radiotherapy and chemotherapy, immunotherapy is the method we put our hopes on. Since its isolation in mid 70s TNF-alpha has been the subject of careful studies investigating its clinical usefulness. In phase I and II clinical trials dose- and manner of administration-dependent side effects were observed, which considerably limited the use of TNF-alpha in clinical practice. Topical (intratumoral) therapy eliminated most systemic side effects. Synergic antitumor efficacy of TNF-alpha, cytokines, such as interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), and cytostatic drugs (etoposide, cyclophosphamide) was proved.

Clinical Trials, Phase I as Topic↗
PubMed2003

Kinetics of gas-phase hydrogen/deuterium exchange and gas-phase structure of protonated phenylalanine, proline, tyrosine and tryptophan.

Site-specific rate constants for the gas-phase hydrogen/deuterium (H/D) exchange of four, three, five and five hydrogen atoms in protonated phenylalanine (Phe), proline (Pro), tyrosine (Tyr) and tryptophan (Trp), respectively, were determined from matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FTICRMS) experiments with D(2)O, D(2)S, and CH(3)OD as deuterating agents. No H/D exchange was observed with D(2)S. For exchange with both CD(3)OD and D(2)O, which is about ten times slower in the latter, results indicate for all compounds protonation of the alpha-amino group in agreement with theoretical results. Also, with both reagents, all compounds exchange at the COOH site more than ten times faster than at the protonation site, with OH and NH sites of Tyr and Trp, respectively, exchanging slowest. The observation of H/D exchange despite the high differences in proton affinities between the amino acids and deuterating agent exceeding 200 kJ mol(-1) is in agreement with lowering of the barrier for proton transfer through hydrogen bonding proposed by Lebrilla and coworkers.

Amino Acids↗