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PubMed1997

Regional isolated perfusion of extremities for melanoma: a 20-year experience with drugs other than L-phenylalanine mustard.

Recurrent melanoma of the extremities can lead to bulky symptomatic lesions that become difficult management problems. Treatment of these tumors with isolated limb perfusion with high dose chemotherapy may offer palliation in a number of patients. Unfortunately, the most commonly used drug, L-phenylalanine mustard, has been known to have significant associated tissue toxicity. Therefore, during the years 1976-1995, we perfused 67 limbs in 60 patients with various other drugs: 36 with dimethyltriazeno imidazole carboxamide, 6 with cisplatin, 20 with carboplatin, and 5 with thiotepa). Perfusion was performed for 16 upper extremities and 51 lower extremities using the pump oxygenator for 1 hour. Among the 60 patients, 17 were treated prophylactically for high-risk melanoma, whereas 43 were treated for local and in-transit recurrences. The technique of perfusion successfully isolated the limbs from the systemic circulation: the median leaks over time were 0.5-1.6 percent for the upper extremities, and 0.2-7.5 percent for the lower extremities. Among the 43 patients treated with therapeutic isolated limb perfusion, 11 patients (26 percent) are alive with no evidence of disease for a median of 58 months (range: 8 months to 17 years 9 months), and another 5 patients (12 percent) are alive with recurrence for a median of 45 months (range: 27 months to 10 years 7 months). Four patients required two perfusions, and two patients required three perfusions (one patient has no evidence of disease 6 years after her third perfusion for recurring in-transit disease). There were 19 complications noted after 14 of the 67 perfusions (21%): postoperative edema, 5; seroma, 4; wound separation/infection, 9; and nonfatal pulmonary embolus, 1. In our experience, aggressive treatment in selected patients with regional isolated perfusion of limbs for melanoma has provided meaningful palliation and salvage of the limbs with adequate disease-free control, and occasional survival benefit. This regional treatment modality is associated with meaningful control and with few serious complications, especially when compared with studies using L-phenylalanine mustard. This series illustrates the safety of controlling limb recurrence with this technique, even with repeat perfusions in the same patient.

Adult↗

PubMed1977

In-situ-isolated perfused rat pancreas: a new method for pharmacological studies of the exocrine pancreas.

A method of in-situ-isolated perfused rat pancreas is described. In situ perfusion of the isolated rat pancreas allows a faster set-up, thanks to a simpler operating procedure. The sensitivity of the isolated rat pancreas has been tested with secretin and cholecystokinin. The pancreas responds to doses of secretin as low as 0.005 CU/kg-h. Such a highly sensitive model might prove to be useful for the bioassay of secretin and the study of the effects of pancreatic secretagogues.

Animals↗

PubMed1992

Papaverine inhibits transcytotic vesicle transport and lipid excretion into bile in isolated perfused rat liver.

Papaverine is a nonspecific smooth muscle relaxant and a phosphodiesterase inhibitor. Its effects on biliary excretion of lipids and horseradish peroxidase were investigated in a single-pass isolated perfused rat liver model. A constant infusion of papaverine (1.6 mumol/min; 40 mumol/L) significantly increased bile flow (microliters per minute per gram of liver) before (2.03 +/- 0.09 vs. 1.0 +/- 0.06) and after sodium taurocholate infusion (2.77 +/- 0.10 vs. 1.88 +/- 0.11). However, papaverine significantly and reversibly reduced biliary excretion of phospholipids and cholesterol (nanomoles per minute per gram of liver) after a 1.0 mumol/min sodium taurocholate infusion, from 7.45 +/- 0.83 and 1.42 +/- 0.15 to 1.75 +/- 0.18 and 0.39 +/- 0.06, respectively (p less than 0.01), whereas secretion of bile acids was unaffected. When a 1-min pulse of horseradish peroxidase (25 mg) was infused in isolated perfused rat liver after a continuous infusion of N6,O-2'-dibutyryladenosine 3',5'-cyclic monophosphate (0.25 mumol/min; 6.25 mumol/L), horseradish peroxidase appeared in bile in an early (4 to 6 min) and late (20 to 25 min) peak. Papaverine significantly reduced the late peak, from 1.211 +/- 0.264 to 0.498 +/- 0.107 (p less than 0.01). Papaverine had no significant effects on either cyclic AMP or cyclic GMP in the liver and bile, although it has been reported that papaverine is a phosphodiesterase inhibitor. These findings indicate that papaverine inhibits biliary excretion of lipids but not bile acids, and they suggest that papaverine has an inhibitory effect on transcytotic vesicle transport independent of an increase of cyclic nucleotides in hepatocytes.

Animals↗

PubMed1983

Synthesis and release of Hageman factor (Factor XII) by the isolated perfused rat liver.

The site of synthesis of Hageman factor (HF, Factor XII) has not been previously demonstrated with certainty. We have studied the production and release of HF in the isolated perfused rat liver and have compared rates of synthesis in this system with absolute rates of degradation measured in vivo. Rat livers, perfused for 5 h with a recycling fluid consisting of a perfluorochemical emulsion (Fluosol 43), were used to demonstrate a cumulative increase of HF in the perfusate as measured by a specific and sensitive radioimmunoassay. The rate of increase in the perfusate pool of HF during the final 4 h of perfusion yielded a mean synthetic rate of 3.5 micrograms/h per 100 g body wt, which was approximately 0.2% of the synthetic rate of albumin in the same system. The cumulative appearance of albumin and transferrin was linear after 1 h and calculated rates of synthesis were 2,012 micrograms/h per 100 g and 263 micrograms/h per 100 g body wt, respectively. De novo synthesis of HF was confirmed by demonstrating incorporation of [14C]lysine into specific immunoprecipitates of HF, and by the observations that both specific incorporation of labeled amino acid and net release of immunoassayable HF were inhibited by the administration of cycloheximide. Finally, it was evident that the rates of synthesis observed in the isolated perfused liver agreed closely with absolute rates of degradation of HF measured in vivo with 125I-rat HF (4.0 micrograms/h per 100 g). From these data we conclude that the liver is the principal site of synthesis of HF.

Animals↗

PubMedDate not supplied

Cardiac and pulmonary effects of alpha tumor necrosis factor administered by isolation perfusion.

AIMS: We studied cardiac and pulmonary function in 22 patients affected by in transit metastases from cutaneous melanoma and metastases from soft tissue sarcoma of the limbs and treated with isolation perfusion in extracorporeal circulation with rTNF alpha at doses ranging from 0.5 to 4 mg/m2 in mild hyperthermia. PATIENTS AND METHODS: All patients experienced a septic-like shock syndrome of variable severity: this feature lasted from 24 to 72 h and was controlled by the infusion of dopamine. Seventeen patients suffered from respiratory insufficiency, which required assisted ventilation (7 cases mechanical ventilation for 1 day, 8 cases for 2 days, and 2 cases synchronized intermittent mandatory ventilation). RESULTS: Spirometric parameters recorded 7-15 days after treatment did not change from baseline values. In contrast, lung transfer factor for carbon monoxide significantly declined in a dose dependent fashion. CONCLUSIONS: Our data confirm that rTNF alpha administered by isolation perfusion technique induces systemic cardiovascular and pulmonary side effects. Further studies are required to better define time course and reversibility of impaired pulmonary function.

Adult↗

PubMed1998

Characterisation, utilisation and clinical relevance of isolated perfused heart models of ischaemia-induced ventricular fibrillation.

The isolated perfused heart has been used increasingly during the last decade as a model for identifying actions of drugs on ventricular fibrillation (VF) induced by myocardial ischaemia. In addition, it has been used to explore the mechanisms responsible for the initiation and maintenance of VF, the concept of endogenous myocardial protection and the phenomenon of preconditioning. This article is a review of the available data (effects of drugs, sources of variation, comparison with other models and man, etc.) and an attempt to evaluate the possible clinical relevance. For several reasons, it is not possible to make a precise judgement on the absolute value of the model in terms of its ability to accurately predict the effectiveness of drugs in the prevention of sudden cardiac death, the main reason being the lack of a positive control, i.e. a drug with proven effectiveness against sudden cardiac death caused by VF in man. Nevertheless, the means by which one may reliably and reproducibly generate ischaemia-induced VF in different isolated heart preparations, and the factors (such as species, heart rate, perfusion constituents and involved zone size) that determine the incidence of VF are now well documented. Careful selection of species and experimental conditions permits the isolated heart of smaller inexpensive animals to function as a first line model for detecting anti-VF activity of probable relevance to phase 1 arrhythmogenesis (i.e., arrhythmogenesis during the first 30 min of ischaemia). In view of the absence of a clinical template from which to evaluate how well it predicts drug effectiveness in man, this model's clinical relevance, like that of all other preparations and models, can yet be neither accepted nor dismissed. Recent publication patterns suggest an increasing use of the model. Therefore, recommendations are made to facilitate its effective use.

Animals↗

PubMed1980

Diuretic and vasoconstrictor effects of sodium orthovanadate on the isolated perfused rat kidney.

Sodium orthovanadate (vanadate) is a powerful inhibitor of (Na+,K+) adenosine triphosphatase and exhibits widespread actions on the renal and cardiovascular systems. In the present study, the effect of vanadate on the functions of the isolated perfused rat kidney was studied. The control parameters for this preparation were: glomerular filtration rate, 225 microliter/min; urine flow, 40 microliter/min; fractional sodium reabsorption, 92%; and total peripheral resistance, 765 kilo pascals/l/min. Varying concentrations of vanadate in the perfusate (0 to 32 microM) produced a dose-dependent rise in glomerular filtration rate, urine flow, total peripheral resistance and inhibition of sodium reabsorption. At higher concentrations, vanadate was nephrotoxic. Since vanadate produces simultaneous rises in glomerular filtration rate and total peripheral resistance, a postcapillary vasoconstrictor effect for the anion is postulated. Clearance of vanadate from the perfusate was determined at various concentrations of the anion in the perfusate and the reversibility of vanadate effect on the kidney was studied. In conclusion, vanadate is a potent diuretic, natriuretic and vasoconstrictor in the isolated, perfused rat kidney and is nephrotoxic at higher dose levels.

Animals↗

PubMed1980

Different effects of hypothermia on insulin and glucagon secretion from the isolated perfused rat pancreas.

Two series of experiments with the isolated perfused rat pancreas were performed in parallel. The conditions differed only with respect to temperature, which was 37.5 degrees C in one series and 28 degrees C in the other. The lowering of the temperature decreased insulin secretion induced by glucose as well as the insulin response to tolbutamide and acetylcholine. Unlike insulin, glucagon secretion was not significantly modified by hypothermia. Our results suggest that the mechanisms involved in glucagon and insulin secretion are different.

Acetylcholine↗

PubMed1986

Effects of ouabain and temperature on cell membrane potentials in isolated perfused straight proximal tubules of the mouse kidney.

In isolated perfused segments of the mouse proximal tubule, the potential difference across the basolateral cell membrane (PDbl) was determined with conventional microelectrodes. Under control conditions with symmetrical solutions it amounted to -62 +/- 1 mV (n = 118). The potential difference across the epithelium (PDte) was -1.7 +/- 0.1 mV (n = 45). Transepithelial resistance amounted to 1.82 +/- 0.09 k omega cm (n = 28), corresponding to 11.4 +/- 0.6 omega cm2. Increasing bath potassium concentration from 5 to 20 mmol/l depolarized PDbl by +24 +/- 1 mV (n = 103), and PDte by +1.6 +/- 0.1 mV (n = 19). Thus, the basolateral cell membrane is preferably conductive to potassium. Rapid cooling of the bath perfusate from 38 degrees C to 10 degrees C led to a transient hyperpolarization of PDbl from -60 +/- 1 to -65 +/- 1 mV (n = 21) within 40 s followed by gradual depolarization by +18 +/- 1% (n = 14) within 5 min. The transepithelial resistance increased significantly from 1.78 +/- 0.11 k omega cm to 2.20 +/- 0.21 k omega cm (n = 15). Rapid rewarming of the bath to 38 degrees C caused a depolarization from -61 +/- 2 mV (n = 17) to -43 +/- 2 mV (n = 16) within 15 s followed by a repolarization to -59 +/- 2 mV (n = 10) within 40 s. Ouabain invariably depolarized PDbl. During both, sustained cooling or application of ouabain, the sensitivity of PDbl to bath potassium concentration decreased in parallel to PDbl pointing to a gradual decrease of potassium conductance.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Conversion of p-tyrosine to p-tyramine in the isolated perfused rat kidney: modulation by perfusate concentrations of p-tyrosine.

We used the isolated perfused rat kidney to evaluate the role of renal decarboxylation of p-tyrosine as the source of urinary p-tyramine. Kidneys were perfused with concentrations of p-tyrosine ranging from 0.02 mM to 2.0 mM. p-Tyramine was measured by a sensitive and specific radioenzymatic assay. An increase in the perfusate concentration of p-tyrosine resulted in a significant increase in p-tyramine production that was blocked by the addition of NSD-1015, an inhibitor of aromatic-1-amino decarboxylase (AADC). We conclude p-tyrosine is the precursor for the renal production of p-tyramine, renal AADC catalyzes the formation of urinary p-tyramine, synthesized p-tyramine is predominantly excreted in the urine, and p-tyramine synthesis is modulated by the arterial delivery of p-tyrosine to the kidney.

Animals↗

PubMed1976

Acetate utilization by the isolated perfused guinea-pig mammary gland.

Acetate uptake by isolated perfused guinea-pig mammary glands was approximately 1.0 mg g-1 h-1 when perfusate acetate concentrations were in the physiological range (5-11 mg/100 ml plasma). At perfusate concentrations below this range (mean 3.62 mg/100 ml plasma) the uptake was not significantly different, but in one experiment in which the mean acetate concentration was 14.5 mg/100 ml plasma the uptake was markedly elevated. Radioactivity from Na (1-14C) acetate was incorporated into CO2 and milk and tissue fat, being largely present in C16 and C18 fatty acids. The guinea-pig is atypical of non-ruminants and similar to ruminants in respect of the blood concentration and mammary utilization acetate.

Acetates↗

PubMed1972

The effects of amino acids on albumin synthesis by the isolated perfused rat liver.

Albumin synthesis was measured in the isolated perfused rat liver by using the livers of both well-fed and starved rats. Starvation markedly decreased albumin synthesis. The livers from starved rats were unable to increase synthesis rates after the addition to the perfusates of single amino acids or the addition of both glucagon and tryptophan. Arginine, asparagine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, threonine, tryptophan and valine, added together to ten times their normal peripheral blood concentrations, restored synthesis rates to normal. The plasma aminogram (i.e. the relative concentrations, of amino acids) was altered by depriving rats of protein for 48h. The use of blood from the deprived rats as perfusate, instead of normal blood, decreased albumin synthesis rates significantly by livers obtained from well-fed rats. The addition of single amino acids, including the non-metabolizable amino acid, alpha-aminoisobutyric acid, to the above mixture increased albumin synthesis rates to normal values. It is concluded that amino acids play an important role in the control of albumin synthesis and that more than one mechanism is probably involved.

Albumins↗

PubMed1993

Glycogenolytic and haemodynamic responses to bovine serum albumin in isolated perfused livers from sensitized rats.

Infusion of BSA into isolated perfused livers of rats sensitized by intraperitoneal injection of BSA led to rapid increases in portal-vein pressure, glucose output and the lactate/pyruvate ratio in the effluent perfusate, with concomitant decreases in oxygen consumption and lactate+pyruvate efflux. The responses were attenuated at low (approximately 7 microM) perfusate Ca2+, but were restored on re-addition of normal Ca2+ concentration. Co-infusion of the cyclo-oxygenase inhibitor ibuprofen (50 microM) or of the platelet-activating factor receptor antagonist WEB 2170 (1.2 microM) inhibited haemodynamic responses to BSA (5 micrograms/ml) by 48% and 59% respectively. Responses to BSA were also attenuated by prior infusion of the beta-adrenergic agonist isoprenaline. Glycogen phosphorylase a activity was increased by 26% in livers freeze-clamped 2 min after onset of BSA infusion; tissue prostaglandin E2 content was increased at 2 min, but returned to control levels at 5 min. Homologous desensitization of hepatic responses to BSA was observed, but heterologous desensitization with heat-aggregated IgG did not take place. It is concluded that livers from rats sensitized to antigen respond directly to subsequent antigen administration by vasoconstriction and glycogenolysis, and that autacoid mediators are involved in these responses.

Animals↗

PubMed1980

Uptake of free choline by isolated perfused rat liver.

The uptake of free choline by isolated perfused rat liver was characterized. A saturable uptake mechanism [Ka = 0.17 +/- 0.07 mM (SD); Vmax = 0.84 +/- 0.16 mumol/min X g dry weight] and a nonsaturable mechanism (through which uptake is proportional to choline concentration in the perfusate) were identified. Most of the choline transported into hepatocytes was converted to betaine, phosphorylcholine, or lecithin. Free choline also accumulated within the intracellular space, suggesting that choline oxidase activity does not always limit choline's uptake by the liver.

Animals↗

PubMed1977

The effect of colloid concentration on the functional characteristics of isolated perfused rat liver.

The volume of bile produced by isolated perfused rat liver was dependent on the concentration of bovine serum albumin (BSA) in the perfusate, the lowest volumes being obtained with Krebs Ringer bicarbonate (KRB alone and with 70 g/l. BSA in KRB. Increasing amounts were produced as the concentration of BSA was reduced from 70 g/l. to 8.5 g/l. The concentration of bile salts in the bile decreased rapidly during the first hour, but much more slowly thereafter. The highest concentration observed during the first hour was with KRB alone and the lowest with 20 g/l. BSA; subsequently, the highest concentrations were obtained with 70 g/l. BSA and the lowest with 20 g/l. BSA. Urea synthesis was lowest with KRB alone, but increased as the concentration of BSA increased; however, values obtained with 8.5, 20, and 40 g/l. were fairly close together. With KRB alone there was a rapid release of potassium during the first hour, but thereafter the rate of release was similar to that found when BSA was present. The lowest concentrations of potassium were obtained with 20 and 40 g/l. BSA. With KRB alone, GOT was released from the start of perfusion of 300 units per minute. With BSA present, GOT release was delayed 4 hours, and thereafter the rate was dependent on the concentration of BSA, being lowest with 20 and 40 g/l. (200 units per min), higher with 8.5 g/l. (350 units per min) and highest with 70 g/l. (400 units per min).

Animals↗

PubMed1963

THE UPTAKE OF NORADRENALINE BY THE ISOLATED PERFUSED RAT HEART.

The uptake of noradrenaline by the isolated perfused rat heart was studied after perfusion with a medium containing various concentrations of (+/-)-[(3)H]-noradrenaline. Simultaneous measurement of the uptake of [(3)H]-noradrenaline and of the net increase in the noradrenaline content of the heart showed that [(3)H]-noradrenaline entering the heart both increased the tissue content and exchanged with endogenous noradrenaline. A large part (about 75%) of the endogenous noradrenaline pool, however, exchanged very slowly if at all with exogenous noradrenaline. The initial rates of noradrenaline uptake satisfied Michaelis-Menten kinetics with a Km for (+/-)-noradrenaline of 6.64x10(-7) M. Further analysis of the uptake process indicated that noradrenaline entered into at least two intracellular pools at different rates. Measurement of the initial rates of noradrenaline uptake during perfusion with various concentrations of nonradioactive (+)- and (-)-noradrenaline showed that the uptake process exhibited stereochemical specificity. The Km values for (+)- and (-)-noradrenaline were 13.9x10(-7) and 2.66x10(-7) M respectively. Cocaine acted as a potent competitive inhibitor of noradrenaline uptake. This finding suggested that diffusion did not play any significant role in the entry of noradrenaline into the tissue.

Antimetabolites↗

PubMed1985

Prostanoids and adrenaline release: a study of [3H]adrenaline efflux from the rabbit isolated, perfused, adrenal gland.

[3H]Adrenaline was incorporated in an isolated perfused preparation of the rabbit adrenal gland and the effects of indomethacin, PGE2 and PGI2 on its release were investigated. Efflux of [3H]adrenaline was elicited by electrical stimulation of the splanchnic nerve (60 s at 5 Hz). Indomethacin (3 and 30 microM) had no effect on stimulation-induced efflux. PGE2 (30, 90 and 300 nM) reduced the efflux; with 90 nM PGE2 the inhibition amounted to approximately 30%. PGI2, in concentrations from 90 to 600 nM, was without effect. These findings indicate that release of [3H]adrenaline from the rabbit adrenal gland is not subject to modulation by endogenous adrenal prostaglandins; however, PGE2 may play a role in some pathological situations.

Adrenal Glands↗

PubMed2003

Interactions among three classes of mediators explain antigen-induced bronchoconstriction in the isolated perfused and ventilated guinea pig lung.

Intravascular challenge of isolated perfused and ventilated guinea pig lung (IPL) from actively sensitized guinea pigs, with cumulatively increasing (10-10,000 microg) doses of ovalbumin (OVA), resulted in dose-dependent and reproducible reductions in lung conductance. The antihistamines mepyramine (1 microM) and metiamide (1 microM), the leukotriene antagonist zafirlukast (0.1 microM), or the cyclooxygenase enzyme (COX) inhibitor diclofenac (10 microM) each caused a parallel and rightward shift in the dose-response relation for OVA, providing evidence for contributions of histamine, cysteinyl-leukotrienes, and COX products to the OVA-induced bronchoconstriction in the IPL. Moreover, when all three drugs were combined there was a complete abolishment of the response to OVA. When two antagonists or inhibitors were combined, the results, however, were more complex. The 5-lipoxygenase inhibitor BAY x1005 (30 microM) and the thromboxane (TP) receptor antagonist BAY u3405 (1 microM) given as single treatment did not inhibit the response to OVA. However, combinations of different antagonists/inhibitors, including BAY x1005 and BAY u3405, caused pronounced inhibitions of the antigen responses, suggesting synergism in action. On the basis of these data it was concluded that although histamine and cysteinyl-leukotrienes mediate the major part of the bronchoconstriction, one or several prostanoids other than thromboxane contribute to the bronchoconstriction evoked by OVA. Moreover, the effect of diclofenac involved a dual action because it also made the IPL less sensitive to histamine and LTD4. The findings resemble and extend recent observations in clinical studies of patients with asthma and support the usefulness of this particular model in airway pharmacology.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗