Treatment of carcinoma of the pancreas with radon seed implantation and intra-arterial infusion of 5-FUDR.
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The interstitial fluid pressure of the submucosa of the gastric fundus was monitored by means of Guyton's capsules in dogs anesthetized with pentobarbital. The intracapsular pressure (ICP) was measured during secretion produced by: a) hypertonic solutions placed inside the stomach; b) arterial hypertension (200 mmHg) applied during intra-arterial infusion of histamine, and c) intra-arterial infusion of acetylcholine. The first procedure did not modify the ICP. On the other hand, whenever interstitial fluid appeared in the gastric lumen during hypertension plus histamine, the mean ICP increased, mostly due to augmented capillary filtration. The hydraulic coefficient measured in these experiments was at least 4 orders of magnitude larger than the respective osmotic coefficient. The action of acetylcholine was complex: large doses enlarged the net capillary filtration, but small doses increased the mean ICP by muscle stimulation only. Contraction of the muscularis mucosae might be the most important mechanism underlying bulk flow of interstitial fluid in physiological conditions. It is concluded that hydraulic gradients across the epithelium might account for the "secretion" of "alkaline" juice.
Intra-arterial infusion of carbamyl phosphate or of carbamyl-DL-aspartic acid into rats on a cariogenic diet greatly stimulated the movement of fluid through the odontoblastic processes. The infusion of sodium cyanate also stimulated fluid movement. Guanidine HCL and L-asparagine were active at higher concentrations. Purifying the urea on a mixed-bed ion exchange resin virtually removed its stimulatory effect on dentinal fluid movement. The action of urea is apparently attributable to contamination with sodium cyanate.
Histamine was infused intra-arterially (10-40 mug/min) into isolated blood perfused canine kidneys while functional and hemodynamic parameters were monitored. When perfusion pressure (PP) was kept constant during the infusion of histamine, renal blood flow (RBF) increased from 137 +/- 9 to 181 +/- 9 ml/min (P less than .001). A greater increase in RBF occurred to the inner renal cortex than the outer renal cortex as measured by radioactive microspheres. The fractional outer/inner cortical blood flow changed from 79:21 before histamine to 74:26 during its infusion (P less than .001). Histamine did not alter creatinine clearance (Ccr), urine volume (V), sodium excretion (UNaV) or the fractional excretion of sodium (FENa) or water (FEH20) under these conditions. When renal blood flow was held constant during the infusion of histamine, PP decreased from 126/106 +/- 2 to 100/81 +/- 2 mm Hg (P less than .001). This resulted in a reduction of absolute outer cortical (outer/inner) changed from 77:23 before histamine to 72:28 during its infusion (P less than .001). In contrast to the effects of histamine at constant PP, CCr, V, UNaV, FENa, and FEH20 were decreased when histamine infusion reduced the PP. Administration of the H1 receptor antagonist, diphenhydramine, blocked the hemodynamic effects of histamine whereas the administration of an H2 receptor antagonist, metiamide, did not alter the histamine response. Similar vasodilatory responses to histamine were observed in isolated blood perfused dog and cat kidneys. In contrast, vasoconstrictor responses to histamine occurred in isolated dog and cat kidneys perfused with Krebs' solution and in isolated rabbit kidneys whether perfused with blood or Krebs' solution.
1. 4-aminopyridine (4-AP, 1 mM) increased noradrenaline (NA) output from the perfused cat spleen at 5 Hz by about fivefold. Enhancement of NA release by 4-AP was reversible. Output of NA induced by potassium was not affected. 2. NA output was doubled at low concentrations (0.1--0.3 mM) of 4-AP, but maximal effect was obtained at 1--3 mM. At 10 mM, it induced spontaneous release of NA which was insensitive to calcium. 3. Insignificant outputs obtained at 5 Hz in 0.1 and 0.3 mM calcium-Krebs solution were markedly enhanced by 4-AP. 4-AP enhanced release at all calcium concentrations up to 5 mM, but maximum output was obtained at 2.5 mM. 4. 4-AP at pH 8.5 was more effective in enhancing NA release than at pH 7.4. 5. 4-AP increased the recovery of intra-arterially infused NA from the control 26 to 47%. 6. 4-AP did not affect release of catecholamines (CA) from the perfused cat adrenal gland by acetylcholine (ACh). 7. It is suggested that 4-AP inactivates potassium current in sympathetic nerves and prolongs the duration of the action potential, thereby allowing a greater influx of calcium ions into the neurone to enhance release of NA.
Total 14C activity in juice secreted by gastric pouches of six dogs and seven isolated canine stomachs was determined in response to intravenous and intra-arterial infusions of histamine and [14C]histamine. The proportions of 14C attributable to histamine, Nalpha-methylhistamine (NalphaMeH), Nalpha,Nalpha-dimethylhistamine (NalphaNalphaMe2H), N-telle-methylhistamine (NtauMeH), imidazole acetic acid (ImAA), N-methylimidazole acetic acid (NtauMeImAA), acetylhistamine (AcH), and histaminol (HOH) were defined using thin-layer chromatography. Similar estimates were made at the end of infusions on blood, gastric mucosa, and gastric muscle. Methylation was the major, or sole, route of metabolism of histamine in the gastric mucosa, and the major product was inactive NtauMeH. Small quantities of the active NalphaMe derivatives, particularly NalphaNalphaMe2H, were identified in both the juice and mucosa. Little or no ImAA, NtauMeImAA, AcH, and HOH were present in juice from isolated stomachs while they did occur in the juice from intact dogs, demonstrating they are extragastric metabolites of histamine. A major mucosal function of methylation of histamine is inactivation, although NalphaMe derivatives formed may play a role in the secretagogue action of histamine.
Several authors have hypothesized that tissue hypermetabolism accounts for increases in ventilation (VE) elicited by 2,4-dinitrophenol. However, some data in the literature indicate that stimulation of VE by isomers of dinitrophenol is unrelated to tissue metabolic rate. To test this latter concept, we compared three different isomers of dinitrophenol (i.e., 2,4-dinitrophenol (2,4-DNP), 2,5-dinitrophenol (2,5,-DNP), 2,6-dinitrophenol (2,6-DNP) with respect to stimulation of VE and with respect to stimulation of oxygen consumption (VO2). In all experiments, 3-4 mg/kg of one dinitrophenol isomer was administered to chloralose anesthetized dogs by intra-arterial infusion. 2,4-DNP elicited large increments in both VE and VO2, 2,6-DNP elicited moderate increments in both VE and VO2, whereas 2,5-DNP elicited small increments in both VE and VO2. These observations demonstrate a correlation between ventilatory and metabolic changes affected by isomers of dinitrophenol. Accordingly, these results are consistent with the hypothesis that ventilatory stimulation by congeners of dinitrophenol is related to tissue hypermetabolism.
Intra-arterial infusion of testosterone-3H gave rise to tritiated dihydrotestosterone, 5 alpha-androstan-3 alpha,17 beta-diol and 5 alpha-androstan-3beta,17 beta-diol in spermatic venous effluent of the perfused rabbit testis-epididymis. Mass spectrometric measurements confirmed that these four androgens were present in spermatic venous effluent of the perfused rabbit testis-epididymis. Gas liquid chromatographic measurement showed that testosterone, dihydrotestosterone, 5 alpha-androstan-3 alpha,17 beta-diol and 5 alpha-androstan-3 beta,17 beta-diol were secreted in similar amounts by the in vitro perfused and in situ rabbit testis-epididymis results obtained by perfusing the testis minus the epididymis suggested that the bulk of these androgens originate from the catabolism of testosterone within the testis rather than the epididymis. Suprisingly, germinal epithelium destruction by heat failed to alter the testosterone, dihydrotestosterone and 5 alpha-androstan-3 alpha,17 beta-diol secretion by the in vitro perfused rabbit testis. In contrast, the secretion of 5 alpha-androstan-3 beta,17 beta-diol was significantly (P less than 0.05) reduced in the same cryptorchid compared to control testes.
Report is made about the combined therapy with cytostatics (methotrexate - bleomycin) and irradiation in patients with extended tumors in the gnathic region. Ten patients in whom a radical therapy with conventional methods did not promise any success, were treated with intra-arterial infusions of methotrexate and bleomycin and simultaneous irradiation. At present, eight patients are tumor free (observation time 4-14 months after termination of therapy). Although radiation doses and doses of cytostatics were high, only insignificant side effects were stated; consequently, the treatment had to be terminated in none of the patients.
BACKGROUND: Endovascular thrombectomy achieves macroreperfusion in large vessel occlusion (LVO) stroke, but only one-quarter of patients had excellent functional outcome. Adjunct intra-arterial (IA) tenecteplase could further improve the treatment effect, yet its efficacy across internal carotid artery (ICA) versus middle cerebral artery (MCA) M1/M2 occlusion remains unclear. OBJECTIVE: To evaluate whether IA tenecteplase improves 90-day functional outcomes in LVO patients stratified by occlusion site (ICA, MCA M1, MCA M2). METHODS: Prespecified secondary analysis of the ANGEL-TNK trial (multicenter, randomized, open-label, blinded endpoint) in 19 Chinese stroke centers. Participants were enrolled who had anterior circulation LVO, 4.5-24 hours from symptom onset, and CT angiography (CTA)/magnetic resonance angiography (MRA)-proven ICA, M1, or M2 occlusion. INTERVENTION: Randomization (1:1) to IA tenecteplase (0.125 mg/kg) or standard medical management after expanded Thrombolysis in Cerebral Infarction (eTICI) 2b50-3 reperfusion. MAIN OUTCOME MEASURE: The primary outcome was the rate of 90-day modified Rankin Scale (mRS) 0-1. RESULTS: There were 256 patients in the trial, including 71 (27.7%) ICA, 122 (47.6%) MCA M1, and 62 (24.2%) MCA M2. ICA occlusion patients treated with IA tenecteplase had higher rates of 90-day mRS 0-1 (39.4% vs 13.2%; relative risk (RR) 2.99; 95% CI 1.51 to 5.96; p=0.002) and mRS 0-3 (54.5% vs 42.1%; RR 1.30; p=0.048) versus controls, with a significant shift toward better mRS scores (median 3 (IQR 1-4) vs 4 (2-6); odds ratio (OR) 2.26; p<0.001). Post hoc analysis showed higher eTICI progression in ICA patients (51.5%) versus MCA M1 (37.9%) and M2 (25.7%). IA tenecteplase had a lower any intracranial hemorrhage within 48 hours in ICA patients (15.2% vs 39.5%; RR 0.38; p<0.001) compared with standard medical management. No significant benefits were observed in the MCA M1/M2 subgroups, and interaction effects were significant between ICA and MCA segments for functional outcomes and safety. CONCLUSIONS AND RELEVANCE: IA tenecteplase had a better functional outcome and lower hemorrhage risk in ICA occlusion compared with standard medical management but not in MCA M1/M2. Occlusion site is a critical determinant of response to IA tenecteplase. A pooled analysis of IA tenecteplase stratified by occlusion site strata is warranted.
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Although experience with drug therapy of advanced or recurrent squamous cell carcinoma of the head and neck is limited, several agents have produced convincing and reproducible tumor regression in these patients. Methotrexate has had the widest usage, and produces 30-50% response rates; bleomycin, hydroxyurea, and adriamycin appear to be somewhat less effective. Location of the malignancy and previous x-ray treatment appear to be important determinants of responsiveness to methotrexate, while degree of differentiation has not yet been shown to be an important factor for response to this drug. Attempts to improve the response rate and duration of chemotherapeutic response by utilizing combinations of drugs, or use of drugs to sensitize the tumor to x-ray treatment, or to reduce the bulk of tumor before x-ray treatment, are reviewed; they have been only moderately encouraging. Intra-arterial chemotherapy appears to have a therapeutic advantage over intravenous treatment; however, the morbidity associated with the former approach limits its usefulness for routine usage. The use of drugs as adjuncts following surgery and/or radiation therapy or immunotherapy are newer approaches that have not been investigated sufficiently, but are promising areas for investigation.
The superior mesenteric blood flow response to intra-arterial injections (0.5-25 mug) and infusions (5-30 mug/min) of 5-hydroxytryptamine (5-HT, serotonin) was investigated in anesthetized cats in which nerve activity to the intestine was altered by surgical and pharmacological procedures. With the superior mesenteric periarterial nerves intact, low doses of 5-HT (less than 5 mug) produce vasodilatation, whereas higher doses produce vasoconstriction. When the periarterial nerves are cut either at the start of or during the experiments, vasodilatation is elicited over the entire dose range, and doses of 5-HT which initially produce vasoconstriction elicit vasodilatation after nerve sectioning and also after alpha-adrenergic receptor blockade. These vascular responses are not secondary to changes in arterial pressure or intestinal motility. The vasodilator response to 5-HT is unaffected by alpha- or beta-adrenergic or cholinergic receptor blockade, by ganglionic blockade, or by histamine receptor blockade, but is blocked by tetrodotoxin and also the 5-HT antagonist, dihydroergotamine.
Fifty patients with a stomach cancer received regional chemotherapy by infusion. Two kinds of cancers were treated with this technique: cancers inaccessible with usual surgical treatment and some limited cancers. In most cases, the catheter was introduced by transcutaneous puncture of axillary artery. According to the site of the cancer, the extremity of the catheter was introduced into the left gastric artery, hepatic artery or coeliac trunk. Efficiency of the infusion was checked by arteriography and by gastric fibroscopic examination with intra-arterial injection of evans blue. The duration of the treatment was two weeks or three weeks. The chemotherapy was made on a sequential method, taking account of the tumoral cellular cycle. The results show an objective response in 80 per cent of the cases, 39 per cent of the non operable cancers were later accessible to surgery. This study shows that chemotherapy should be used in the treatment of any stomach's cancers before surgical treatment.
Servocontrol of mechanical ventilation using systemic arterial blood pH, measured by a dual-function pH/PCO2 intra-arterial sensor, as the controlled variable uas carried out in 30 dogs anesthetized with pentobarbital, 30 mg/kg. The control loop consisted of the animal, an intra-arterial dual-function pH/PCO2 sensor and sensor amplifier, a controller, and a Siemans-Elema 900 servoventilator. The system responded appropriately to changes in set-point pH from 7.30 to 7.50, as well as to infusions of lactic acid, which, with the control loop open, decreased systemic arterial blood pH 0.1 TO 0.2 PH units. Long-term (16 hr) ventilation of one dog with the systemic arterial blood pH servocontrol ventilator was shown to be feasible.
Impromidine (SK & F 92676) has recently been identified as a potent and specific histamine H2-receptor agonist. The present paper describes some cardiovascular studies with the drug. Impromidine lowers blood pressure in cats and rats by interaction with H2-receptors. During continuous intravenous infusions of impromidine, the fall in blood pressure is due to a reduction in total peripheral resistance; cardiac output increases during hypotension. The responses to impromidine are similar to responses to histamine in mepyramine-treated cats. Impromidine administered intra-arterially also causes vasodilatation in the femoral and mesenteric vasculature by interaction with H2-receptors. Impromidine stimulates all measured parameters including coronary flow in the isolated working heart of the guinea-pig. Dose-response curves to impromidine were displaced to the right in the presence of cimetidine.
Simultaneous hemodynamic and blood gas measurements were performed in 26 hypertensive adults, who were cigarette smokers, before and after a 30-minute infusion of saralasin (5 microgram/kg/min) which is a highly specific competitive antagonist of angiotensin II (AII). The arterial pressure fell in nine, rose in seven and was unchanged in ten patients. The mean cardiac index for the entire group remained unchanged. Pulmonary arterial or wedge pressure, pulmonary vascular resistance, arterial PCO2 and pH did not change. Unrelated to the hemodynamic changes, the mean arterial oxygen pressure (PaO2) increased from 68.6 +/- 2.2 mm Hg to 73.9 +/- 2.1 mm Hg (P less than 0.001). In the absence of a significant increase in alveolar ventilation as indicated by an unchanged mean PCO2 and lacking a hemodynamic explanation, the mechanism for the rise in PaO2 is speculative at this stage. The possibility of an improvement in the distribution of ventilataion by saralasin infusion is under investigation.