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Biomedical subjects

D Platt

Publications and source records attributed to D Platt.

At least 289 records · Page 16Linked to original sources
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Clinical pharmacology in the elderly - an example of interdisciplinary cooperation between basic research and clinic.

Elderly patients with multiple diseases are often more sensitive to the effects of drugs than younger ones. The simultaneous ingestion of various drugs can invite drug interactions. Moreover, age-induced physiological and pathological changes can influence pharmacokinetics and pharmacodynamics. Compared with earlier periods of life, we still know very little about pharmacokinetics and pharmacodynamics in old age; it follows that in patients with multimorbidity closer monitoring and a more accurate diagnosis, before drug therapy is instituted, are of far greater importance than wholesale prescription and the isolated treatment of individual diseases against the background of multiple pathology.

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Pharmacokinetics of nimodipine in multimorbid elderly patients with chronic brain failure.

Twenty-one elderly patients with chronic brain failure received a single 30 mg oral dose of the calcium channel blocker nimodipine followed by two weeks of 30 mg three times a day (t.i.d.) administration. The aim of this study was to assess if drug accumulation occurred in our frail elderly subjects under this dose regimen. Plasma concentrations of nimodipine and three main metabolites were determined by gas chromatography. During the 2-week period we did not find significant changes in peak plasma concentrations and corresponding areas under the plasma concentration-time curves. Trough nimodipine plasma concentrations before administration of the morning dose were similar on days 7 and 14. Therefore, no evidence of drug accumulation was found. Blood pressure and heart rate remained stable throughout the study period and no adverse effects were observed. During the study period, there was a decline in the proportion of patients who complained about dizziness and insomnia. Overall, our data suggest that there is no need to alter the usual adult dose of nimodipine if this drug is administered to multimorbid frail elderly patients suffering from chronic brain failure.

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On the efficacy of piracetam in geriatric patients with acute cerebral ischemia: a clinically controlled double-blind study.

Using a randomized, double blind group comparison, the efficacy and tolerance of piracetam as an additional therapy of hydroxyethyl starch, venous infusion and low dose heparin treatment, which are the basis of therapy in our hospital, has been studied in patients displaying acute cerebral ischemia. A total of 56 patients were enrolled, of whom 27 were given piracetam and 29 served as a control during a 28-day period. Using single photon emission computer tomography (SPECT) analysis, we observed that in 23 piracetam-treated patients (85.2%) a reduction in the area of brain regions displaying an impaired flow rate occurred (P < 0.001; Fisher's exact two-sided test). Only six of placebo-treated patients (20.7%) showed an improved flow rate. Analysis of the recorded computer tomography map gave an improvement coefficient >2 (flow rate marginally or better improved) for 23 piracetam patients as compared with 5 placebo patients (P < 0.001, Uleman test).

Clinical Trial↗
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Effective lovastatin therapy in elderly hypercholesterolemic patients - an antioxidative impact?

The effect of 3 months lovastatin therapy on serum lipids, apolipoproteins, alpha-tocopherol and red cell membrane fatty acid pattern was assessed in twelve elderly ambulatory patients (mean age 70.9+/-8.0 years) with hypercholesterolemia type IIa according to Fredrickson. After a run-in period of 4 weeks without drug therapy, the patients were given a daily dose of 20 mg lovastatin. The treatment resulted in statistically significant decreases in mean serum low density lipoprotein cholesterol (LDL-CH, -34%), in the atherogenic index LDL-CH/HDL-CH (-35%) and in the concentration of apolipoprotein B (-26%). No change in the vitamin E status, as related to plasma total lipids, was observed during the 3 months of therapy. The fatty acid pattern of phospholipids from red cell membranes showed an increase in linoleic acid metabolites and a decrease in the precursor linoleic acid, indicating an induction of fatty acid desaturases by lovastatin. In addition, an increase in the plasmalogen portion of erythrocyte membrane phospholipids was exhibited by increases in the proportion of fatty aldehyde dimethyl acetals (DMA) in the fatty acid pattern. The plasmalogens increase may counteract the slow but consistent decrease in their concentration in red cell membranes and human aortas with increasing donor age and in arteriosclerosis. Since plasmalogens may function as physiological antioxidants, the observed increase in DMA concentration might reflect a previously unrecognized antioxidative principle of a lovastatin therapy.

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Interleukin-6 and selected plasma proteins in healthy persons of different ages.

In the present study, interleukin-6 (IL-6) and several acute phase proteins were measured in healthy participants (23-87 years of age). A linear correlation between IL-6 and age was established with an increase of 0.016 pg/ml (0.004) per year of life. Whereas CRP remained below 0.5 mg/dl in all participants, an increase with age for fibrinogen and an inverse relation for albumin as well as transferrin were obtained. However, the increase of IL-6 did not correlate with any of these changes. IL-6 associated diseases may therefore occur more often with advancing age, but in healthy participants IL-6 does not explain the changing plasma protein pattern resembling that of an acute phase reaction.

Acute-Phase Proteins↗
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Seizure induced C-Fos mRNA in the rat brain: comparison between young and aging animals.

The molecular mechanisms associated with age-related alterations in the pharmacological and physiological properties of hippocampal and cortical neurons in response to chemically induced seizure are largely unknown. Administration of pentylenetetrazole (PTZ) (50 mg/kg body weight) to rats of various ages evoked tonic-colonic seizures. Using RNA gel blot analysis we found that 1 h after the onset of seizure, the mRNA for the protooncogene c-fos was increased in the hippocampus and cortex of 3-month-old rats. The levels of c-fos mRNA in the hippocampus and cortex of 3-month-old rats returned to control levels by 3 h after PTZ administration. The levels of c-fos mRNA in the hippocampus and cortex of 20-month-old and 30-month-old rats peaked at 3 h and returned to basal levels by 15 h following PTZ treatment. These results suggest that the induction of immediate-early gene expression, as exemplified by c-fos, is not impaired in the aged rat brain. However, the aged rat brain responded more slowly to chemically induced seizure and the levels of c-fos mRNA induction are decreased by about 49% in the cortex and by 27% in the hippocampus of 30-month-old rats, as compared to the levels expressed by 3-month-old rats.

Aging↗
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Evidence that V+ fibronectin, GFAP and S100 beta mRNAs are increased in the hippocampus of aged rats.

In the present study, using RNA gel-blot analysis, we characterized the developmental changes in the prevalence of mRNA coding for fibronectin (FN), glial fibrillary acidic protein (GFAP), neurotrophic protein S100 beta, and beta-actin mRNA in rat hippocampus and forebrain from 1 to 720 days of age. We found that the FN and mRNA containing the V segment (FN-V) was relatively abundant at early postnatal stages, but very few transcripts were detected in adult rats. However, the hybridization signal for the juvenile FN-V mRNA was up to approximately 8-fold increased in some but not all 24-versus 6-month-old rats. Also, GFAP and S100 beta transcripts were faintly expressed at an early developmental stage, then the level of expression steadily increased starting with day 21. The greatest increase averages approximately 1.8-fold for GFAP in 24-month-old rats, and approximately 1.5-fold for S100 beta in 15-month-old versus 6-month-old rats. As all these messages are localized primarily in astrocytes, we conclude that (a) astrocyte might play an active role in aging hippocampus and (b) an increase in S100 beta and GFAP mRNA expression may precede that for FN-V mRNA expression in a hypothetical pathway of molecular events underlying neurodegeneration in the hippocampus of old rats. We also note the considerable variability among the 24-month-old rats, suggesting that aging is an individual process.

Actins↗
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Effect of including recommendations for antimicrobial therapy in microbiology laboratory reports.

Innovative approaches are needed to improve cost-effective antibiotic use in hospitals. We established an algorithm to provide a recommendation for both a single oral and a single parenteral antimicrobic, including dosage, to be placed in the bacteriology laboratory report for therapy guidance of 174 episodes of lower respiratory infection in a group of "program" patients with no evidence of infection at other sites. The initial recommendation was based on the Gram-stained direct smear of secretions. The recommendation was updated when preliminary culture results were available, and again with final identification and susceptibility data. We compared the severity of illness, length of stay, and cost of therapy for 68 episodes in program patients who received the recommended therapy with 111 episodes in a control group of patients who received antimicrobial therapy but for whom no recommendations were reported. There was a significantly greater use of the recommendations for sicker patients. Antimicrobial therapy, in general, was more often used for the program patients than for the controls. There was no difference in length of stay or therapy cost. We recommend that this approach be used in settings where there is more problematic use of antimicrobics.

Algorithms↗
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Proteoglycan metabolism of equine articular chondrocytes cultured in alginate beads.

Equine chondrocytes were cultured in vitro for 30 days in ionically gelled alginate beads. The alginate polymerises into a stable gel in the presence of divalent cations (calcium), and rapid depolymerisation in the presence of a calcium chelator releases the viable chondrocytes. The chondrocytes maintained a spherical appearance for 30 days in culture, in marked contrast to monolayer cultures, which develop a dedifferentiated fibroblastic morphology. The major proteoglycan molecule produced by the encapsulated chondrocytes was aggrecan, of similar hydrodynamic size to aggrecan molecules present in the matrix of the articular cartilage from which the cells were harvested. Link protein, keratan sulphate and chondroitin sulphate were also synthesised by the chondrocytes, as demonstrated by immunohistochemistry. The proteoglycan secreted by the chondrocytes consisted of at least two pools, one remaining adjacent to the cell and forming a dense, cell-associated matrix, and another migrating more peripherally into the intercellular compartment. Newly synthesised proteoglycans extracted from the pericellular matrix and the intercellular matrix were similar in hydrodynamic size and aggregated in the presence of exogenous hyaluronan.

Alginates↗
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Effect of borage oil consumption on fatty acid metabolism, transepidermal water loss and skin parameters in elderly people.

Human skin is not able to biosynthesize gamma-linolenic acid (GLA, 18:3omega6) from the precursor linoleic acid (LA), or arachidonic acid (AA) from dihomo-gamma-linolenic acid (DHGLA). Dietary supplementation with GLA-rich seed oil of borage skips the step of hepatic 6-desaturation of fatty acids (FA) and, therefore, compensates the lack of these essential FA in conditions with impaired activity of delta 6-desaturase. Twenty-nine healthy elderly people (mean age 68.6 years), received a daily dose of 360 or 720 mg GLA for 2 months, using Borage oil in gelatine capsules (Quintesal 180, manufacturer Galderma Laboratorium GmbH, Freiburg, Germany). The effects of fatty acids derived from ingested borage oil capsules on skin barrier function were assessed by measurement of transepidermal water loss (TEWL). The consumption of borage oil induced a statistically significant improvement of cutaneous barrier function in the elderly people, as reflected in a mean decrease of 10.8% in the transepidermal water loss. Thirty-four percent of the people noted itch before borage oil consumption and 0% afterwards. Dry skin was claimed to be reduced from 42 to 14%, but no significant alteration of skin hydration was measured. The FA-composition of erythrocyte membrane phospholipids demonstrated an increase of GLA (+70%) and DHGLA (+18%) and a reduction of saturated and monounsaturated FA. There was no significant alteration in nervonic acid or in AA content, but an increase in the DHGLA/AA ratio (+23%). Thus, the consumption of borage oil by elderly people lead to alteration of FA metabolism and improved skin function.

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Influence of age and treadmill running on motor performance in rats.

The influence of treadmill running on age-dependent changes of motor performance was investigated in differently old female Sprague-Dawley rats. Following 12 months of exercise training a test battery including gait analysis, spontaneous motor activity, and three more motor tasks of different complexity was performed. The influence of age on motor performance depended on the complexity of the motor requirement. Simple tests were less affected by age than more complex ones. Treadmill running induced positive effects on the age-dependent impairment of various motor functions in middle-aged (14-18 months old) and aged (23-27 months old) rats. The positive influence of exercise training is explained by benefits of endurance training to the cardiovascular, neuromuscular, and central nervous systems.

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Specific interchain cross-linking of antibodies using bismaleimides. Repression of ligand leakage in immunoaffinity chromatography.

The extensive use of antibody-containing affinity columns in the purification of biologically active compounds (e.g., genetically engineered proteins) is severely hampered by the leaching of antibody (or portions thereof) from the immunoaffinity resin during elution of the target antigen. One of the major problems in this context is the combined use of reducing (i.e., thiols) and chaotropic (e.g., detergents and denaturants) agents in the elution step, which causes the disassociation of heavy and/or light chains from the immobilized antibody, thereby contaminating the resultant product. In order to overcome this problem, we have cross-linked the four antibody chains at their sites of disulfide interlinkage, thus producing a single antibody chain. To accomplish this, interchain disulfide bonds were reduced, and the resultant thiol groups were cross-linked by using bifunctional SH-specific reagents (particularly bismaleimides). Cross-linking of up to 95% of the available SH groups produced was achieved with concomitant retention of antigen-binding activity. The cross-linked antibody was immobilized onto CNBr-activated Sepharose, and the resultant column was found to be substantially more stable to harsh elution conditions than similar columns which contain the un-cross-linked antibody.

Antibodies↗
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Age-dependent changes of the kidneys: pharmacological implications.

About 40% of the intoxications after drug administration occur in the elderly. A significant proportion of the disease states in elderly patients is related to adverse reactions to prescribed drugs. Declining renal function, a reduction in both renal blood flow and glomerular filtration rate, is a major contributor to drug toxicity in the elderly. Therefore, a review (based on newer papers from Medline) of age-dependent changes of the kidneys and their consequences for drug therapy in geriatric patients is presented. Renal changes that occur with aging are: a decrease of renal weight, a thickening of the intrarenal vascular intima, sclerogenous changes of the glomeruli, and infiltration of chronic inflammatory cells and fibrosis in the stroma. Altered renal tubular function, including impaired handling of water, sodium, acid, and glucose, is also frequently present in old age. Impaired 'endocrinologic' functioning manifested by changes of the renin-angiotensin system, vitamin D metabolism, and antidiuretic hormone responsiveness has been reported. The aging kidney is constantly exposed to the effects of a variety of potential toxic processes, i.e., drugs and chronic illnesses including hypertension, diabetes, and atherosclerotic disease. Renal changes that occur with aging also consist of impairment in the ability to concentrate urine and to conserve sodium and water. These physiological changes increase the risks of volume depletion and prerenal type of acute renal failure. A frequent cause of acute renal failure in the elderly is drug-induced nephropathy. Nonsteroidal anti-inflammatory drugs, antibiotics, and diuretics are most often involved. Due to the age-dependent decline of renal function, the pharmacokinetics of many drugs are altered in elderly patients. Therefore, the most important renal function to monitor with aging is the creatinine clearance. Changes in pharmacokinetics of many drugs and most decisions on drug dosage can be based on this information alone, as tubular functions of the kidney decrease at rates paralleling the age-dependent decrease in glomerular filtration rate (which is approximately measured by the creatinine clearance). As a conclusion, age-dependent changes of renal function are not only responsible for changes in pharmacokinetics and pharmacodynamics. In many cases, the kidneys are the target organ of adverse drug reactions too.

Aging↗
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The aging liver: structural and functional changes and their consequences for drug treatment in old age.

BACKGROUND/OBJECTIVE: Numerous age-related changes in hepatic structure and function have been described, although liver function seems to be quite well maintained in old age. Few consistent and reproducible observations and a lack of correlation between structural and functional data characterize the present state of our knowledge. In contrast to renal clearance, no equally reliable method exists to estimate hepatic drug clearance. The contribution of age to altered drug clearance in the elderly is difficult to assess as drug interactions, numbers and types of drugs taken at a time, underlying disease and increased interindividual variability are superimposed to the aging process. METHODS: A comprehensive computer-assisted search of the literature. RESULTS: A decline in liver volume and blood flow and a reduction in in vitro and in vivo metabolic capacity have been shown in older subjects, and the physiologic basis of reduced hepatic drug clearance in this age group. CONCLUSIONS: After decades of research into the matter, the old and well-known aphorism "start lower--go slower" is valid more than ever in the field of geriatric prescribing. Not only renally excreted drugs but also substances which are metabolized and excreted by the liver should be used at a starting dose which is 30-40% smaller than the average dose used in middle-aged adults.

Aged↗
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Temporal dynamics of degenerative and regenerative events associated with cerebral ischemia in aged rats.

BACKGROUND AND PURPOSE: The age-related decline in plasticity of the brain may be one factor underlying the poor functional recovery after stroke. In the present work we tested the hypothesis that the attenuation of neural plasticity could be the result of an age-related REDUCTION in the upregulation of factors promoting brain plasticity (microtubule-associated protein 1B [MAP1B], beta-amyloid precursor protein [betaAPP]), and an age-related INCREASE in glial reactivity and the accumulation of Abeta, a proteolytic cleavage product of betaAPP with neurotoxic properties. METHODS: Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague-Dawley rats. The functional outcome was assessed in neurobehavioral tests 3, 7, 14 and 28 days after surgery. At the indicated time points, brains were removed and immunostained for glial cells. Abeta, as well as the markers of brain plasticity, betaAPP and MAP1B. RESULTS: Histologically, in young rats there was a gradual activation of both microglia and astrocytes that peaked by days 14-28 with the formation of a glial scar. In contrast, aged rats showed an accelerated astrocytic and microglial reaction that peaked in the first week after stroke. The expression patterns of a growth-associated phenotype of betaAPP as well as with MAP1B accumulation in varicosities along axons in cortical areas affected by stroke peaked between days 14 and 28 in young animals. In aged rats their expression was both delayed (28 days) and reduced. In addition the carboxy terminal fragment of betaAPP steadily accumulated over time and reached a maximum by day 14 in aged rats as compared to 28 days in young rats. CONCLUSIONS: These results suggest that a temporally anomalous gliotic reaction to cerebral ischemia in aged rats in conjunction with a late and limited upregulation of neuronal plasticity proteins as well as a diminished neurogenesis potential lead to the prevalence of scar tissue that impedes functional recovery from stroke.

Aging↗
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Age influences the expression of GAP-43 in the rat hippocampus following seizure.

BACKGROUND: Normal aging is associated with impairments in learning and memory and motor function. One viable hypothesis is that these changes reflect an age-related decrease in brain plasticity. OBJECTIVE: The aim of the present study was to identify age-related changes in the time course of expression of the axonal growth associated protein 43 (GAP-43) in a rat model of brain plasticity. METHODS: We examined by Northern blotting, in situ hybridization, and immunohistochemistry the effects of age on the time course of the expression GAP-43 following pentylenetetrazole-induced seizure in the hippocampus of 3-, 18-, and 28-month-old rats. RESULTS: In this model of brain plasticity, young rats displayed a decrease in GAP-43 mRNA levels in CA1, CA3, and polymorphic regions, lasting from 10 h to 3 days after seizure. This was followed by recovery, with peak expression between days 10 and 20. The baseline levels of GAP-43 mRNA decreased with age, especially in the CA3 region. Despite lower baseline levels, middle-aged rats showed the same pattern of upregulation of GAP-43 mRNA expression as the young animals. Old rats showed only minimal upregulation, however, and this occurred only in the polymorphic layer. The level GAP-43 protein itself was higher in old control rats than in the other two control groups, a condition that was transiently reversed by seizure activity. CONCLUSIONS: Middle-aged rats are still capable of a sustained, though diminished, response to seizure activity, while old rats lose this ability. Disruption of the temporal and anatomical coordination of expression of GAP-43 may contribute to the general decline in brain plasticity with age.

Age Factors↗
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Age-dependent red cell phagocytosis and activity of the rabbit reticulohistiocytic system.

The rate of phagocytosis of 59Fe-labeled erythrocytes of various ages was measured in the rabbit. Liver, spleen and the remaining parts of the reticulohistiocytic system (RHS) were compared with each other. The phagocytic activity in the liver increased from 66% in 4-day-old to nearly 90% in 70-day-old erythrocytes, whereas the radioactivity decreased in the other parts of the RHS from 33 to 3%. In the spleen, the radioactivity increased from 1.7 to 7.6%. On the 8th day, the radioactivity in the liver temporarily amounted to 92%, reducing that of the other organs. Comparison of the phagocytic activity per gram showed a ratio of liver to spleen of 1:2 after 4 days which changed to 1:5 after 70 days.

Animals↗