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Biomedical subjects

A Pacini

Publications and source records attributed to A Pacini.

At least 37 records · Page 2Linked to original sources
PubMed1987

Studies on tumor necrosis factor (TNF)--I. Pharmacokinetics of human recombinant TNF in rabbits and monkeys after intravenous administration.

By intravenous (bolus) administration of human recombinant tumor necrosis factor (2.5 X 10(6) units) into rabbits and monkeys it has been possible to follow its decay in the plasma and to determine the pharmacokinetic parameters. After labelling TNF with 125I, simultaneous determination of protein-bound radioactivity and bioactivity was carried out with the result that radioactivity decays somewhat slower than bio-activity suggesting that the use of the former tracer alone may underestimate TNF catabolism. Simultaneous determination of 125I-TNF in rabbit plasma and lymph after intravenous and subcutaneous administration indicated a lymph to plasma TNF concentration ratio of about 0.1 and 1 or more for the two routes, respectively.

Animals↗
PubMed1987

Studies on tumor necrosis factor (TNF). III. Plasma disappearance curves after intramuscular, subcutaneous, intraperitoneal, and oral administration of human recombinant TNF.

Since clinical trials with TNF as a therapeutic agent for cancer are in progress, in this study we have chosen to compare the metabolic characteristics of 125I-labeled and unlabeled RTNF after administration through IM, SC, IP and PO routes. Both RTNF and 125I-RTNF plasma concentration profiles showed an absorption phase and a biexponential decline common to all routes of administration. Moreover the pharmacokinetic analysis indicates that TNF blood levels following SC injection are rather similar to those seen after IM dose. No difference has been found in T max. In contrast, the Kel is apparently increased in the SC route, but the difference is not significant. While a prolonged absorption phase had been obtained after IP injection of RTNF, comparison of t 1/2 beta and Kel between IP and SC or IM route failed to reveal significant differences. Surprisingly some plasma TNF bioactivity has been detected following oral administration.

Administration, Oral↗
PubMed1987

DNA synthesis and interferon release by human peripheral lymphocytes exposed to high potassium medium.

Lymphocytes have their membrane potential changed during transition from the resting to the active state. On these grounds, we investigated the response of human peripheral lymphocytes to a depolarizing high-potassium (102.7 mM) medium, by assaying cellular incorporation of labeled thymidine and interferon (IFN) release in the culture medium. The greatest effect is evident 3-4 days after preincubation for 120 min in high K+ medium. A temporal correlation has been observed between rate of DNA synthesis and IFN production. The IFN activity is shown to be gamma-type.

Cells, Cultured↗
PubMed1987

Studies on tumor necrosis factor (TNF): II. Metabolic fate and distribution of human recombinant TNF.

We have evaluated the fate of cold and 125I- human recombinant tumor necrosis factor (RTNF) using isolated organs such as rabbit and monkey livers and rabbit kidney and lungs. We have also evaluated the body distribution of the total radioactivity after iv administration of 125I-RTNF in the rabbits. Monkey and rabbit livers play little catabolic role for RTNF. Lungs do not catabolize TNF at all, while the kidney appears to be the main catabolic organ. Accordingly, the body distribution of 125I-RTNF shows that most of the radioactivity is concentrated in the kidneys.

Animals↗
PubMed1985

Pharmacokinetics of human lymphoblastoid interferon in rabbits.

By intravenous (bolus) administration of large amounts (29 Mega Units) of lymphoblastoid interferon into rabbits, it has been possible to detect circulating antiviral activity (0.02% of the dose) up to 18 hr post-injection and to determine for the first time the pharmacokinetic parameters. The slow component (elimination phase) has a half-life of 235 +/- 9 min. The total apparent volume of distribution is 2,564 +/- 1,497 ml which is far larger than the combined plasma-extracellular volumes. This suggests a IFN dilution due to its extensive binding to cell receptors. The clearance of 7.3 +/- 4.1 ml/min is an index of the rate of renal and cellular (internalization of the receptor-ligand complex) catabolism of IFN. Pharmacokinetic parameters are useful for devising an administration schedule of IFN as an antiproliferative agent but are not predictive of an immunological response if IFN is used as an immuno-adjuvant.

Animals↗
PubMed1985

Catabolic sites of human interferon-gamma.

Recombinant human interferon-gamma (HuIFN-gamma) injected into rabbits disappeared from the circulation more rapidly than natural IFN-gamma. The latter displayed an initial decay curve more rapid than that for natural HuIFN-alpha although 4 h after injection plasma levels were similar. This result suggests that IFN-gamma has pharmacokinetic properties different to those of IFN-alpha which may be explained by considerable and simultaneous hepatic and renal catabolism. Surprisingly, the hepatic uptake of recombinant (unglycosylated) IFN-gamma was more marked than uptake of natural IFN-gamma. Moreover, both IFN-gamma preparations were cleared by the isolated and perfused kidney and once again the recombinant IFN disappeared more rapidly. This result does not conform with the suggestion that IFN-gamma exists as a tetramer which would not be filtered by the glomerulus, but is consistent with the pharmacokinetic behaviour shown in vivo.

Animals↗
PubMed1984

Pulmonary catabolism of interferons: alveolar absorption of 125I-labeled human interferon alpha is accompanied by partial loss of biological activity.

The catabolism of interferon was examined in isolated rabbit lungs which were ventilated and perfused with homologous blood. Natural human interferon-alpha (HuIFN-alpha) from lymphoblastoid Namalwa cells or recombinant DNA-derived HuIFN-alpha 2 were labeled with 125I, mixed with an excess of the respective cold interferons and added to the perfusion blood. Protein-bound and acid-soluble radioactivity, as well as antiviral activity, were measured at regular time intervals. During the first 3 h of perfusion, only very small fractions of the interferons disappeared from the perfusate, irrespective of whether lungs were inserted in the perfusion system. This indicated that catabolism of interferons in the pulmonary circulation was negligible. On the other hand, when the interferons were instilled into the bronchial-alveolar tree, absorption of antiviral activity differed from that of acid-precipitable protein-associated radioactivity. While most of the radioactivity was transferred into the perfusate, only 2% of antiviral activity of natural HuIFN-alpha and 30% of that of HuIFN-alpha 2 were recovered in the perfusate. In both cases acid-soluble radioactivity in the system reached about 10%. Since radioiodide, instilled in the bronchial-alveolar tree, was transported rapidly into the perfusate, this type of analysis did not help in locating the site(s) of degradation. Alveolar macrophages did not catabolize or inactivate interferons in vitro.

Animals↗
PubMed1983

Renal metabolism of homologous serum interferon.

The metabolic behaviour of homologous native and desialylated serum and urinary interferons has been investigated by using an isolated and perfused rabbit kidney, the performance of which is comparable to that in vivo. Serum native and urinary interferons disappear from the plasma perfusate with a fractional turnover rate of 1.8 and 2% and half-lives of 3 and 35 min, respectively. Serum desialylated interferon disappears much more rapidly in keeping with the finding that the glomerular sieve poses less steric hindrance and electrophysical repulsion to the passage of less anionic proteins. These results confirm and extend our previous findings, which indicated that the kidneys have a predominant catabolic role and can explain to some extent the rapid disappearance of interferon from plasma.

Animals↗
PubMed1983

Degradation of human 125I-interferon alpha by isolated perfused rabbit kidney and liver.

Rabbit livers and kidneys were isolated and perfused with homologous blood. After equilibration, human IFN alpha labeled with 125I and an excess of cold IFN alpha were added, and blood samples were withdrawn at predetermined times. Protein-bound and acid-soluble radioactivity together with biological (antiviral) activity were measured. Our results show that although liver exerts a minimal catabolism, the kidney filters and breaks down a considerable amount of IFN alpha. The parallelism between protein-bound radioactivity and biological activity decay curves indicates that IFN carefully labeled with 125I can be reliably used for metabolic investigations.

Animals↗
PubMed1982

The kidney is the main site of interferon catabolism.

The fate of human natural interferons alpha and beta and of recombinant (R) alpha 2 has been investigated by using an isolated and perfused rabbit kidney preparation with a normal physiological performance. A remarkable amount of IFN is filtrated in a monoexponential fashion, reabsorbed and very likely degraded in tubular cells with negligible excretion in the urine. The disappearance rate of HuRIFN-alpha 2 is higher than natural HuIFNs-alpha and beta and is in keeping with the lower molecular weight of RIFN-alpha 2. Differences in molecular charge or shape are probably responsible for the slightly reduced filtration of IFN-beta. Pharmacokinetic studies in animal models appear instructive and useful for devising improved dosage schedules in clinical trials.

Animals↗
PubMed1982

The role of liver in the catabolism of human alpha- and beta-interferon.

The susceptibility of human leukocyte (alpha), fibroblast (beta) and recombinant alpha-2-interferons to clearance by the isolated and perfused rabbit liver has been evaluated. Human leukocyte and recombinant alpha-2-interferons were stable and their initial levels were maintained in the perfusate even if they had been treated with neuraminidase, thus suggesting that alpha-interferons have no exposed sugars recognizable by hepatic binding proteins. On the other hand, native, and particularly desialylated human beta-interferon, underwent marked hepatic uptake confirming the importance of the liver as a catabolic site for glycosylated interferons.

Animals↗
PubMed1981

Renal filtration, absorption and catabolism of human alpha interferon.

The renal handling of human interferon-alpha has been evaluated by using an isolated and perfused rabbit kidney. IFN-alpha disappears from plasma with a t1/2 of 81 min and the fractional turnover rate is 0.84%/min. About 47 molecules of IFN-alpha are filtrated with 100 molecules of creatinine but most of the IFN is absorbed by tubular cells. This is the first report showing that human IFN-alpha is filtrated by the kidney, largely absorbed, most probably catabolized within tubular epithelium and excreted in negligible amounts with the urine.

Animals↗
PubMed1981

Renal metabolism of rabbit serum infection.

Three different approaches have been used to evaluate the catabolism of rabbit serum interferon (IFN) by the kidneys. Firstly, in normal rabbits the disappearance of exogenous IFN from plasma was very rapid, whereas it was significantly slower after bilateral nephrectomy. Secondly, the IFN level in arterial blood was always higher than in renal venous blood: the mean renal extraction rate of IFN in the rabbit, with a renal plasma flow of 9 ml/min, was about 1 ml/min. Thirdly, a selective and reversible tubular damage induced by maleate before intravenous administration of IFN significantly inhibited luminal uptake of IFN and markedly increases the interferonuria. All of these results support the view that the kidneys have a preponderant role in IFN filtration, catabolism and excretion.

Animals↗
PubMed1980

Poor performance of the isolated rabbit kidney perfused with free-cell media and whole blood.

All of these results indicate that the isolated rabbit kidney, perfused either with free-cell media or with whole blood, shows marked functional deficiencies and cannot be considered a reliable preparation. The former media do not induce vasoconstriction but are unable to insure a correct cations reabsorption, while the latter causes intense renal vasospasm and clogging of the glomerular circulation indicated by high arterial pressure and hematuria. On the basis of these observations it appears indispensable to use a perfusion medium capable of eliciting renal autoregulation but deprived of blood elements such as platelets and leukocytes that may be either directly or indirectly responsible for the glomerular clogging. This problem is considered in the following communication.

Animals↗