PubMed Health⌕ Search

Biomedical subjects

H D Danenberg

Publications and source records attributed to H D Danenberg.

At least 19 recordsLinked to original sources
PubMed2001

Viral neuroinvasion as a marker for BBB integrity following exposure to cholinesterase inhibitors.

Exposure to the nerve agent soman, an irreversible cholinesterase (ChE) inhibitor, results in changes in blood-brain barrier permeability attributed to its seizure-induced activity. However, smaller BBB changes may be independent of convulsions. Such minor injury may escape detection. A nonneuroinvasive neurovirulent Sindbis virus strain (SVN) was used as a marker for BBB permeability. Peripheral inoculation of mice with 2 x 10(3) plaque forming units (PFU) caused up to 10(5) PFU/ml viremia after 24 hours with no signs of central nervous system (CNS) infection and with no virus detected in brain tissue. Intra-cerebral injection of as low as 1-5 PFU of the same virus caused CNS infection, exhibited 5-7 days later as hind limb paralysis and death. Soman (0.1-0.7 of the LD50) was administered at peak viremia (1 day following peripheral inoculation). Sublethal soman exposure at as low as 0.1 LD50 resulted in CNS infection 6-8 days following inoculation in 30-40% of the mice. High virus titer were recorded in brain tissue of sick mice while no virus was detected in healthy mice subjected to the same treatment. No changes in the level of viremia or changes in viral traits were observed in the infected mice. The reversible anticholinesterases physostigmine (0.2 mg/kg, s.c.) and pyridostigmine (0.4 mg/kg, i.m.) injected at a dose equal to 0.1 LD50, induced similar results. Thus, both central and peripheral anticholinesterases (anti-ChEs) induce changes in BBB permeability sufficient to allow, at least in some of the mice, the invasion of this otherwise noninvasive but highly neurovirulent virus. This BBB change is probably due to the presence of cholinesterases in the capillary wall. SVN brain invasion served here as a highly sensitive and reliable marker for BBB integrity.

Alphavirus Infections↗
PubMed2001

Formulation and delivery mode affect disposition and activity of tyrphostin-loaded nanoparticles in the rat carotid model.

Poor drug residence in the arterial wall hinders clinical implementation of local drug delivery strategies for the treatment of restenosis. A rat carotid model of vascular injury and intraluminal delivery of tyrphostin-containing polylactic acid (PLA) nanoparticles (NPs) were used to determine the relationship between residence properties and biological activity of different formulations and administration modes. The effects of delivery modes (denudation and delivery time) and formulation variables (adsorbed vs encapsulated drug, and NP size) on arterial drug/NP retention were examined. Antirestenotic effects of large (160 nm) and small (90 nm) tyrphostin-containing NPs, surface-absorbed tyrphostin, and systemic treatment were compared. Fluorescent NPs were used to study the spatial distribution of the carrier in the arterial wall. The decrease in arterial tyrphostin level over time fitted a biexponential model. Delivery time and pressure, endothelium integrity, particle size, and drug-polymer association affected local pharmacokinetics and the antirestenotic results after 14 days. The PLA-based tyrphostin NP formulation ensured a prolonged drug residence at the angioplasty site after single intraluminal application. Several readily adjustable formulation and procedural factors considerably modified arterial ingress of the drug-loaded NPs and governed their subsequent redistribution, tissue binding, elimination, and ensuing antirestenotic effect.

Animals↗
PubMed2000

Acute myocardial infarction--a late complication of intracoronary stent placement.

BACKGROUND: Myocardial infarction (MI) as the first indication of postangioplasty restenosis is extremely rare, and it has been speculated that the fibroproliferative restenotic lesion is less likely to undergo plaque rupture than the lipid-laden native atherosclerotic lesion. HYPOTHESIS: The present study was designed to examine whether intracoronary stent implantation affects this course. METHODS: In all, 994 consecutive patients who underwent angioplasty and intracoronary stent implantation in our hospital were reviewed retrospectively for the occurrence of MI. RESULTS: Eight patients (0.8%), all male and hypertensive, aged 33-83 years, presented with an MI due to stent occlusion more than 30 days following stenting (range: 35-398 days). In two patients, MI occurred 3 and 5 h, respectively, following completion of a maximal high-level exercise test that was negative for ischemia. Angiography revealed complete occlusion or significant stenosis of the stent in all eight patients, with an obvious intimal dissection in either edge of the stent in six patients. Except for gender and hypertension, no correlation was found with other risk factors, vessel involved, initial angiographic results, or with stent design, diameter, or length. CONCLUSIONS: Myocardial infarction as a late complication of successful stent implantation occurred in 0.8% of our patients. This is only the lower bound of the estimated frequency for such an event. We hypothesize that the transition point between the relatively fixed stent and the normal artery is exposed to high deformation stress which makes it vulnerable to rupture and dissection. Strenuous exercise and hypertension may increase the deformation stress and the risk of intimal rupture.

Adult↗
PubMed1999

Dehydroepiandrosterone selectively inhibits production of tumor necrosis factor alpha and interleukin-6 [correction of interlukin-6] in astrocytes.

Dehydroepiandrosterone (DHEA) is a native neurosteroid with immunomodulating activity. DHEA effectively protects animals from several viral, bacterial and parasitic infections and it was suggested that its age-associated decline is related with immunosenescence. In the present study we examined the ability of DHEA to inhibit the production of inflammatory mediators by mycoplasma-stimulated glial cells and to change the course of acute central nervous system (CNS) inflammatory disease in vivo. Addition of DHEA (10 microg/ml) markedly inhibited tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production (98 and 95%, respectively), whereas nitric oxide (NO) and prostaglandin E2 (PGE2) production was not affected. However, daily administration of 0.5 mg DHEA to mice or 5 mg to rats did not change the clinical outcome of experimental autoimmune encephalomyelitis (EAE).

Adjuvants, Immunologic↗
PubMed1999

Acute myocardical infarction due to delirium tremens.

A 36-year-old patient with normal-appearing coronary arteries suffered an acute Q-wave myocardial infarction during acute alcohol withdrawal and delirium tremens. Sympathetic hyperactivity with coronary spasm and increased platelet reactivity are probably the underlying mechanisms.

Adult↗
PubMed1998

The influence of sequential annual vaccination and of DHEA administration on the efficacy of the immune response to influenza vaccine in the elderly.

The present study examined the effect of repeated vaccination and of dehydroepiandrosterone (DHEA) treatment on the immune response to influenza vaccine in elderly subjects. Seventy-one elderly volunteers, aged 61-89 years, enrolled in a prospective randomized, double-blind study to receive either DHEA (50 mg qd p.o. for 4 consecutive days starting 2 days before immunization) or placebo. Antibody response against the three strains of vaccine was measured before and 28 days after vaccination, and compared between previously vaccinated and non-vaccinated subjects. DHEA treatment did not enhance established immunity. A significant decrease in attainment of protective antibody titer (titer of 1:40 or greater) against A/Texas in subjects with non-protective baseline antibody titer was recorded following DHEA treatment compared to placebo (52 vs. 84%, P < 0.05). Post-immunization titers against influenza A strains were significantly higher in those subjects who were never immunized before. Additionally, post-vaccination protective titers against the A/Johannesburg strain were more prevalent in those subjects who were never vaccinated before. The results were not the same for anti-B/Harbin antibodies-repeated vaccination caused a non-significant increase in HI titer in previously vaccinated subjects.

Adjuvants, Immunologic↗
PubMed1998

Pharmacodynamic and pharmacokinetic rationales for the development of an oral controlled-release amoxicillin dosage form.

The goal of this investigation was to develop an oral sustained-release formulation for amoxicillin that would maximize the duration of active drug concentration in the extracellular fluid, thus increasing the dosing interval while assuring antimicrobial activity. This rationale is based on the pharmacodynamic properties of the drug which is non- concentration dependent on the one hand, while requiring long exposure of the pathogen to the drug with minimal post-antibiotic effect on the other. Due to pharmacokinetic constraints, including short biological half-life and limited 'absorption window' (confined to the small intestine) with poor colonic absorption, the new matrix tablet formulation, composed of hydrophilic (hydroxypropyl methyl-cellulose) polymer, was designed to release 50% of its contents within the first 3 h and to complete the drug release process over 8 h (under in vitro conditions). The pharmacokinetics of the new formulation was evaluated in 12 healthy volunteers and compared to a conventional gelatin capsule with both formulations containing 500 mg amoxicillin. The plasma concentrations of active amoxicillin and penicilloic acid were determined by an HPLC method with a fluorometric detector. It was found that the area under the concentration-time curve and maximal serum amoxicillin concentrations following the sustained release preparation were lower than the immediate release formulation. However, the time over the required threshold concentrations, i.e. the minimal inhibitory concentration (MIC) as well as the more clinically relevant parameter--four times MIC of the drug against susceptible pathogens, was found to be maintained for significantly longer periods. The results suggest that in order to achieve a twice daily dosing regimen that will provide therapeutic concentrations for the whole 12 h dosing intervals, a larger dose of the new formulation should be given (e.g. 750 mg or even 1 g twice daily). This recommendation is based on the large interindividual differences of the extent of amoxicillin absorption found in this investigation, and is intended to assure that the 'poor' absorbers will also benefit from full antibiotic efficacy. This dosing regimen will lead to increased patient compliance and improved therapeutic outcome.

Administration, Oral↗
PubMed1997

[Salbutamol intoxication].

A 20-year-old asthmatic woman who ingested 300 mg of salbutamol (Albuterol) and 30 g of paracetamol is presented. She had sinus tachycardia up to 160/min, hypotension (80/50 mmHg), tremor, hypokalemia (2.1 mEq/l) and hyperglycemia (12.1 mEq/l). Treatment was by gastric lavage, fluids, potassium and N-acetylcysteine. Symptoms resolved in 24 hours.

Adrenergic beta-Agonists↗
PubMed1997

Tachycardia, orthostatic hypotension and profound weakness due to concomitant use of fluoxetine and nifedipine.

The use of the selective serotonin reuptake inhibitor fluoxetine is associated with only minor cardiovascular effects. However, due to a possible inhibitory effect on the metabolism of calcium channel blockers it may potentiate the activity of nifedipine, causing profound adverse cardiovascular effects. This report describes the appearance of profound weakness, orthostatic hypotension and tachycardia following the initiation of fluoxetine treatment in a nifedipine-treated 80-year-old patient.

Aged↗
PubMed1997

Dehydroepiandrosterone treatment is not beneficial to the immune response to influenza in elderly subjects.

BACKGROUND: Dehydroepiandrosterone (DHEA) is a native steroid with an immunomodulating activity that was suggested to counter-regulate some phenomena of immunosenescence. Recently, it was shown to reverse the age-associated decline of immune response against influenza vaccine in aged mice. The present study was designed to evaluate the effect of DHEA on the immunization of elderly volunteers against influenza. METHODS: Seventy-one elderly volunteers age 61-89 yr were enrolled in a prospective randomized, double-blind study to receive either DHEA (50 mg qd p.o. for four consecutive days starting two days before immunization) or placebo. Antibody response to the vaccine was measured before and 28 days after vaccination. RESULTS: DHEA treatment significantly increased serum DHEA-sulfate (DHEA-S). No enhancement in established immunity was observed. A significant decrease in attainment of protective antibody titer (1:40 or higher) against the A/Texas strain in subjects with nonprotective baseline antibody titer was recorded following DHEA treatment compared with placebo (52% vs. 84%, P < 0.05). Baseline DHEA-S serum levels were inversely related to attainment of immunization in DHEA-treated subjects. Influenza-like morbidity during the winter was low in the study group with no difference between the DHEA and placebo groups. CONCLUSIONS: Although highly effective in aged rodents, a short course of DHEA treatment did not improve the age-related declined response to immunization against influenza in human subjects. Higher baseline DHEA-S levels are not predictive of better immunization against influenza in the elderly.

Aged↗
PubMed1996

Dehydroepiandrosterone (DHEA) increases production and release of Alzheimer's amyloid precursor protein.

Dehydroepiandrosterone (DHEA), the major secretory product of the human adrenal cortex, significantly declines with advanced age. We have previously demonstrated that DHEA prevents the reduction in non-amyloidogenic APP processing, following prolonged stimulation of the muscarinic receptor, in PC12 cells that express the ml acetylcholine-receptor. The present study examined whether this effect may be mediated via modulation of APP metabolism. It was found that DHEA treatment increases the content of membrane-associated APP holoprotein by 24%, and the accumulation of secreted APP in the medium by 63%. No increase in viable cell number nor in nonspecific protein production was observed in DHEA-treated cells. Thus, DHEA seems to increase specifically both APP synthesis and secretion. We propose that the age-associated decline in DHEA levels may be related to the pathological APP metabolism observed in Alzheimer's disease.

Alzheimer Disease↗
PubMed1995

Dehydroepiandrosterone enhances influenza immunization in aged mice.

The effect of DHEA administration on the age-associated decline in immunity against influenza vaccine was studied. Increased humoral response was observed in 16- and 24-month-old mice immunized by live A/PR/8/34 (H1N1) influenza virus following DHEA treatment (a single injection adjacent to immunization). Furthermore, DHEA-treated mice demonstrated increased resistance to postvaccination intranasal challenge with live influenza virus. Thus, DHEA treatment overcomes the age-related defect in the immunity of old mice against influenza.

Aging↗
PubMed1995

Dehydroepiandrosterone augments M1-muscarinic receptor-stimulated amyloid precursor protein secretion in desensitized PC12M1 cells.

Epidemiologic studies suggest that the age-related decline in dehydroepiandrosterone (DHEA) levels may be associated with Alzheimer's disease (AD). Cholinergic markers also decline with age, and are associated with AD pathology. Activation of m1AChR-transfected PC12 cells (PC12M1) with cholinergic agonists results in secretion of Alzheimer's beta-amyloid precursor protein (APP) which in turn reduces beta-amyloid production. This study examined whether DHEA affects APP processing in m1AChR-transfected PC12 cells. DHEA treatment did not significantly alter basal or m1AChR-stimulated APP secretion. However, DHEA (0.1 microM) significantly diminished the desensitization of APP secretion in cells exposed to carbachol for 24 h. The effect of DHEA on APP processing is probably not related to up-regulation of m1AChR or increased m1AChR-activated phosphoinositide hydrolysis since these parameters did not change following DHEA treatment. These findings imply a possible involvement of DHEA in APP processing. Thus, the age-associated decline in DHEA levels may contribute to decreased APP secretion and a consecutive increase in beta-amyloid deposition, which in turn may play a role in the development of AD.

Amyloid beta-Peptides↗
PubMed1995

NGF promotes amyloid precursor protein secretion via muscarinic receptor activation.

Processing of beta-amyloid precursor protein (APP) is coupled to several neurotransmitter receptors, including m1 muscarinic (m1AChR), and is associated with decreased amyloid deposition. Muscarinic agonist-stimulated APP secretion and membrane APP were measured in control and in NGF-differentiated PC12 cells stably transfected with m1AChR. This secretion was markedly enhanced following treatment with 50 ng/ml NGF for 3 days, and was observed using either carbachol or the M1-selective agonist AF102B. The effects of NGF were reflected by larger reductions in membrane-associated APP levels following muscarinic stimulation. These observations imply that M1 muscarinic receptors may act in concert with NGF to boost APP processing, and M1-selective agonists may thus be beneficial for reducing amyloid deposition by NGF-responsive neurons.

Amyloid beta-Protein Precursor↗
PubMed1995

Criteria to assess in vivo performance of sustained release products: application to diltiazem formulations.

The three classical pharmacokinetic parameters used to assess bioequivalence, AUC (total area from zero to infinity), Cmax (peak plasma concentration), and tmax (time to reach Cmax), are suitable to determine the extent and rate of absorption of immediate-release drug products. However, they may fail to evaluate the pharmacokinetic performance, particularly the rate of absorption of sustained-release (SR) formulations, which yield flat plasma curves with multiple peaks. This paper evaluates the inclusion of the following criteria for bioequivalence assessment of diltiazem SR formulations: MRT (mean arithmetic time), Cmax/AUC, peak occupancy time (POT), t(apical) (the arithmetic mean of the times associated with the concentrations within 25% of Cmax), C(apical) (the arithmetic mean of the concentration within 25% of Cmax), percent fluctuation and flatness of the curve as assessed by the coefficient of variation of the Css (steady state concentration) values obtained during a dosing interval at steady state. The above proposed criteria, as well as the classical parameters AUC, Cmax, and tmax were utilized in a recent pharmacokinetic study of a new SR product of diltiazem, Dilapress 240 (formulation A). Formulation A was analyzed following single (240 mg) and multiple (240 mg qd for 6 days) dosing at steady state (day 6) in comparison to Cardizem CD (formulation B). The bioavailability of formulation A relative to that of formulation B following single and multiple dosing was 92 +/- 28% and 90 +/- 24%, respectively. The 90% confidence intervals (Cl) over a mean AUC ratio of 89% were 78-101% (single dose, SD) and 77-101% (multiple dose, MD). following the administration of formulations A and B, identical mean values of the peak plasma concentration were obtained: 84 ng/mL (SD) and 132 ng/mL (MD). The 90% Cl over a mean Cmax ratio of 100% were 83-115% (SD) and 86-115% (MD). In the SD study, subject 8 had a relative bioavailability value of 24%, which deviated by 7.5 standard errors (SE) from the mean AUC ratio. Consequently, we repeated the single dose analysis without subject 8. The mean bioavailability data was 97 +/- 37% with a 90% Cl of 80-114% over a mean AUC ratio of 92%. ANOVA analysis did not show any formulation or period effect in all tested pharmacokinetic parameter s. On the basis of these results, these two formulations were judged to be bioequivalent. In contrast to the AUC and Cmax ratio, the 90% Cls associated with the ratio of the proposed criteria, with the exception of C(apical), did not fall within the acceptable limits. In the current study, a discrepancy was found between the above pharmacokinetic parameters, which were examined concerning their ability to detect differences in bioequivalence between SR products and the classical parameters regularly used for bioequivalence assessment. Although the parameters examined are theoretically more attractive than the single point parameters Cmax and tmax for rate of absorption assessment, their utility in bioequivalence would require further examination.

Adult↗