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Prostaglandin E1 in peripheral vascular disease: A PET study of muscular blood flow
Abstract
Increase of blood flow in the ischaemic leg is believed to represent the main action of prostaglandin E1 (PGE1) in the therapy of peripheral vascular disease (PVD). There is no reliable data in man concerning the amount of increase in muscular blood flow (MBF) of the calf, and the difference between intra-arterial and intravenous application.
We conducted a positron emission tomography (PET) study of MBF with 15O-water as flow tracer. Fifteen patients with PVD and three healthy volunteers were given 5 micrograms PGE1 intra-arterially over 50 min; PET scans were taken at 0, 25 and 50 min. Additionally, eight of the patients were investigated during an intravenous infusion of 40 micrograms PGE1 over 120 min; PET scans were taken at 0, 30, 60 and 120 min.
Increase of muscular blood flow by intra-arterial PGE1 averaged 80%. A steal phenomenon was not observed. The amount of flow enhancement depended on whether or not the femoral artery was patent. During intravenous PGE1, muscular blood flow remained unchanged.
In man, the pharmacodynamic profile of intra-arterial PGE1 differs clearly from intravenous PGE1. The flow-enhancing property is lost during metabolization in the lung. Since no difference exists between the therapeutic efficacy of intraarterial and intravenous PGE1, the impact on muscular blood flow is not as important as suggested previously.
... 10,11 The inability to deliver high prostaglandin concentrations to peripheral vascular beds may limit the beneficial local hemodynamic actions of prostaglandin dosing. 12 Therapeutic administration of prostaglandins results in systemic vasodilation with resultant hypotension and other related adverse responses. 10 Despite these limitations, results from several trials have suggested that prostaglandins may have efficacy in CLI. ...
Purpose:
Eicosanoids with vasodilating and angiogenic properties have been postulated to be effective therapies for critical leg ischemia (CLI) secondary to atherosclerotic peripheral arterial disease. The ability to deliver active drug to the site of action at adequate doses for sufficient duration has been a major limitation in the clinical development of such therapies. Lipo-ecraprost is a lipid-encapsulated prostaglandin E1 prodrug with the potential to deliver active prostaglandin to the site of critical arterial ischemia. The current trial was designed to test the hypothesis that lipo-ecraprost would improve amputation-free survival in patients with CLI who had no revascularization options.
Methods:
The study was randomized, multicenter, double blind, and placebo controlled. Patients who met clinical and hemodynamic criteria were randomized to receive placebo or lipo-ecraprost (60 microg) administered intravenously on each of 5 days per week, for a total of 8 weeks. The study's primary endpoint was the rate of a composite end point of death or amputation above the level of the ankle at 180 days (6 months).
Results:
The study was terminated on a recommendation from the Data and Safety Monitoring Board after the completion of a protocol-specified interim analysis for futility. At the time of termination, 383 of the planned 560 patients had been randomized, of which 379 received at least one dose of study medication and thus were included in the intention-to-treat population. Twenty-three patients were lost to follow-up and were not available for 6-month assessments. At 6 months of follow-up, there were 23 amputations in the 177 patients who received placebo, and 29 amputations in the 179 patients randomized to lipo-ecraprost. At 6 months, 10 deaths had occurred in the placebo group and 18 deaths had occurred in the lipo-ecraprost arm. Changes in lower-extremity hemodynamics over the 6-month study period did not differ between the placebo and lipo-ecraprost treatment arms.
Conclusion:
Intensive treatment with lipo-ecraprost failed to modify the 6-month amputation rate in patients with CLI who were not candidates for revascularization.
Thermography is the examination or recording of an image of the variations in surface temperatures of an object by detecting the infrared radiation emitted by this object. Its high sensitivity enables the early detection of ischaemic disorders and the monitoring of therapy dynamics and its outcome. This study was performed to evaluate the use of thermography in the assessment of peripheral arterial occlusive disease, and monitoring of patient treatment. The study included two groups of 20 patients. Group I: 20 active pilots from military helicopters, following regular medical examination by the Central Aviation-Medical Commission. Group II: 20 patients with chronic ischemia of the lower extremities. Patients treated with sulodexin have also been studied prior to, and after therapy. In all patients thermography and Doppler ultrasound were performed, and the rate of arterial pressure at the ankle to that in brachial artery (ABI) measured. In the clinical group of patients thermography revealed a decrease in mean lower leg temperature by 1.1-1.4° C, in comparison with the mean temperature of the same area in healthy pilots. Immediately after therapy, the mean temperature increased by 0.6-0.8° C. ABI before the treatment was decreased by 0.18-0.87, and after therapy increased by 0.05-0.25°C (mean 0.15) in comparison with the initial values. Clinical examination has shown a marked prolongation of the distance the patients were able to walk without claudication. Thermography is a valuable additional diagnostic tool in the assessment of peripheral blood flow and may be used to monitor the outcome of the treatment.
To establish whether muscle blood flow (MBF) measurements with O-water positron emission tomography could reliably identify patients with critical limb ischemia and detect and quantify a distal deficit in skeletal MBF in these cases.
O-water positron emission tomography scans were performed at rest or during unloaded ankle plantar and dorsiflexion exercise of the diseased leg in 17 subjects with leg ischemia or on a randomly selected leg of 18 age-matched healthy control subjects. TcPO2 was evaluated with Novametrix monitors and perfusion of skin topically heated to 44 degrees C and adjacent nonheated areas with a Moor Instruments laser Doppler imaging scanner.
The enhancement of MBF induced by exercise was significantly lower in ischemic than in normal legs, and the sensitivity and specificity of this phenomenon were similar to those of laser Doppler imaging or TcPO2 in identifying ischemia subjects. In addition, the exercise MBF deficit was predominant at the distal-leg levels, indicating the ability of the technique to help determine the correct level of amputation.
Skeletal MBF of legs with severe ischemia can be detected accurately with O-water positron emission tomography and could add valuable information about viability of skeletal muscle in the residual limb when deciding the level of an amputation.
Administration of L-arginine improves nitric oxide (NO) formation and endothelium-dependent vasodilation in atherosclerotic patients.
We investigated in this double-blind, controlled study whether prolonged intermittent infusion therapy with L-arginine improves the clinical symptoms of patients with intermittent claudication, as compared with the endothelium-independent vasodilator prostaglandin E1, and control patients.
Thirty-nine patients with intermittent claudication were randomly assigned to receive 2 x 8 g L-arginine/day, or 2 x 40 microg prostaglandin E1 (PGE1)/day or no hemodynamically active treatment, for 3 weeks. The pain-free and absolute walking distances were assessed on a walking treadmill at 3 km/h, 12% slope, and NO-mediated, flow-induced vasodilation of the femoral artery was assessed by ultrasonography at baseline, at 1, 2 and 3 weeks of therapy and 6 weeks after the end of treatment. Urinary nitrate and cyclic guanosine-3', 5'-monophosphate (GMP) were assessed as indices of endogenous NO production.
L-Arginine improved the pain-free walking distance by 230+/-63% and the absolute walking distance by 155+/-48% (each p < 0.05). Prostaglandin E1 improved both parameters by 209+/-63% and 144+/-28%, respectively (each p < 0.05), whereas control patients experienced no significant change. L-Arginine therapy also improved endothelium-dependent vasodilation in the femoral artery, whereas PGE1 had no such effect. There was a significant linear correlation between the L-arginine/asymmetric dimethylarginine (ADMA) ratio and the pain-free walking distance at baseline (r=0.359, p < 0.03). L-Arginine treatment elevated the plasma L-arginine/ADMA ratio and increased urinary nitrate and cyclic GMP excretion rates, indicating normalized endogenous NO formation. Prostaglandin E1 therapy had no significant effect on any of these parameters. Symptom scores assessed on a visual analog scale increased from 3.51+/-0.18 to 83+/-0.4 (L-arginine) and 7.0+/-0.5 (PGE1; each p < 0.05), but did not significantly change in the control group (4.3+/-0.4).
Restoring NO formation and endothelium-dependent vasodilation by L-arginine improves the clinical symptoms of intermittent claudication in patients with peripheral arterial occlusive disease.
A prospective, randomised study was undertaken to investigate the effect of intravenous infusion of either iloprost, the stable prostacyclin (PGI2) analogue, or alprostadil (prostaglandin E1) on peripheral resistance (PR) during femoro-distal reconstruction.
A prospective randomised study was performed with 35 patients. The PR Measurement of peripheral resistance involved a silicon tube temporarily inserted between the donor and recipient vessel. A flowmeter probe and a pressure transducer were inserted into the tube. The peripheral resistance was calculated as a quotient of pressure and flow under approximate physiological conditions. Patients received either alprostadil (4.4 ng/min/kg) or iloprost (2 ng/min/kg) intravenously over ten minutes. After the end of the infusion, the measurements were taken for five minutes.
Baseline peripheral resistance was similar for both groups (iloprost 0.76+/-0.54 mmHg/ml/min, alprostadil 0.72+/-0.35 mmHg/ml/min, p>0.05). Following the measurement procedure, the final peripheral resistance in the iloprost group was reduced (0.57+/-0.33 mmHg/ml/min), but the difference to the alprostadil group (0.70+/-0.36 mmHg/ml/min) was not significant (p>0.05). The different decrease of ratio peripheral resistance (quotient between final and baseline resistance times one hundred) was highly significant (iloprost: 79.4+/-13.4% vs alprostadil: 97.0+/-15.6%, p<0.01).
Intravenous application of prostanoids, infused with usual doses over ten minutes during femoro-distal reconstructions, produces significant differences in decrease of peripheral resistance. Alprostadil only causes a slight drop of resistance, whereas iloprost causes a significant higher reduction of peripheral resistance.
Objective measures of recruitable blood flow are of importance in angiogenesis trials. We validated a new PET-derived flow reserve (FR) measurement in healthy subjects and subjects with peripheral artery disease (PAD).
Five healthy volunteers and 5 subjects with PAD underwent cannulation of the femoral artery and vein. Basal and maximal flow (100 micro g/kg/min of adenosine infused intraarterially) in the lower extremity was determined using thermodilution (TD) techniques. Subjects then underwent plethysmography (PL) followed by PET measurements of blood flow at the calf level. For the PET studies, a transmission scan followed by injection of 1.85 GBq (50 mCi) H(2)(15)O and dynamic scanning for 5 min were acquired in five 1-min frames. Regions of interest were drawn on successive PET image slices, and radioactivity was quantified from the first-minute scan after injection. FR for each of the 3 modalities was expressed as the ratio of adenosine to basal flow.
PET-derived FR correlated strongly with TD (r = 0.82; P = 0.004) but not with PL (r = 0.17; P = 0.85). The mean average difference in FR between healthy volunteers and PAD subjects was 13.0 with PET and 4.5 with TD. The intra- and intersubject variability for PET expressed as the coefficient of variation was 10.5% and 29.0% for healthy subjects and 7.0% and 52.9% in PAD, respectively.
As expected, FR was significantly lower in PAD subjects compared with healthy subjects as assessed with TD and PET but not with PL. PET-derived FR appears to be reproducible and generates sharper and higher indices of recruitable flow in healthy subjects and PAD. These findings have implications for the use of PET-derived FR as a sensitive index of recruitable flow in angiogenesis trials.
A noninvasive method that employs 15O-water and positron-computed tomography (PCT) was used to measure quantitative local cerebral blood flow (1CBF) in man. 15O-Water (about 30-50 mCi) was introduced through a single-breath inhalation of 15O-carbon dioxide or through an intravenous bolus injection of 15O-water. A sequence of five 2-min PCT scans was initiated at the time of tracer administration. A series of 15-20 blood samples (1 ml each) was withdrawn from the radial artery of the subject over a period of 10 min. Oxygen-15 radioactivities in the blood samples were immediately counted in a well counter to give an input function, which together with the projection data collected by PCT were processed to provide images of 1CBF and local water distribution volume. The method was found to be convenient to use and gave good-quality images of 1CBF. Quantitative values of lCBF in images were 59 ± 11 and 20 ± 4 ml/min/100 g for gray and white matter, respectively, with a gray-to-white matter ratio of 2.93 and a global flow value of 42 ± 8 ml/min/100 g. Distribution volume of water was 0.85 ± 0.03, 0.76 ± 0.03, and 0.81 ± 0.02 ml/g respectively, for gray matter, white matter, and whole brain.Keywords: Key Words:; Cerebral blood flow; Distribution volume of water; 150-water; Positron computed tomography.
With the advent of a new generation of PET scanners that have introduced whole-body PET to the clinical setting, there is now more interest in developing protocols for the evaluation of both intracranial and somatic cancers. The value of PET in clinical oncology has been demonstrated with studies in a variety of cancers including colorectal carcinomas, lung tumors, head and neck tumors, primary and metastatic brain tumors, breast carcinoma, lymphoma, melanoma, bone cancers, and other soft-tissue cancers. A summary of current clinical applications of PET in oncology is presented with special attention to colorectal, lung, and intracranial neoplasms since the majority of clinical trials have focused on these cancers. A variety of radiopharmaceuticals are described that are currently included in clinical tumor-imaging protocols, including metabolic substrates such as fluorine-18-fluorodeoxyglucose and carbon-11-methionine, and analogs of chemotherapeutic agents such as fluorine-18-fluorouracil and fluoroestradiol. An attempt is also made to include examples of clinical trials that demonstrate response to therapeutic intervention. The increasing number of oncologic PET studies reflects the growing interest in functional imaging in oncology.
To assess quantitatively regional nutritive muscular blood flow in patients with peripheral vascular disease (PVD), we evaluated the utility of PET with 15O-water.
Eight healthy volunteers and 16 patients with angiographically proven PVD were studied. Regional blood flow of the calf was measured with 15O-water PET during rest, after intra-arterial infusion of prostaglandin E1 and during ergometry. The studies were quantified using a one tissue compartment model.
Normalized mean tracer uptake from 15-60 sec correlated closely (r = 0.98) with absolute blood flow. Scan times longer than 90 sec were required to determine blood flow reliably. The flow values were overestimated by 2% if arterial blood volume was neglected or if the input function delay was corrected globally for parametric imaging. Mean blood flow of calf muscles at rest did not differ significantly between patients (0.017 +/- 0.006 ml/min/ml) and control subjects (0.018 +/- 0.010 ml/min/ml). In PVD patients, blood flow increased by 100% after intra-arterial infusion of PGE1 in the respective leg. In the control subjects, average flow increased by a factor of six during exercise. The increase was more pronounced in the extensor muscles (0.182 +/- 0.031 ml/min/ml) than in flexor muscles (0.121 +/- 0.045 ml/min/ml). Due to the specific type of ergometry, superficial flexors exhibited higher flow values than the profound ones.
PET with 15O-water enables reliable determination of regional nutritive skeletal muscle blood flow for research and clinical applications in patients with PVD.
Prostaglandin E1 (PGE1) was infused into anesthetized dogs in aorta or i.v. in doses from 0.12 to 1.2 μg/kg/min. In all dogs a reproducible fall in blood pressure and increase in heart rate was obtained. Administration in aorta produced more pronounced changes than i.v. administration and infusion high in aorta was more effective than low in aorta. Infusion of PGE1 into a common carotid artery elevated the blood pressure slightly in 6 of 8 dogs. PGE1 produced a fall in blood pressure also in dogs treated with the sympathetic ganglionic blocking agent AgentitR and reserpine and with the beta-adrenergic receptor blocking agent, propranolol (InderalR). In the AgentitR-treated animals infusion of PGE1 into a common carotid artery produced a blood pressure fall, similar to that seen during i.v. infusion. There was no increase in heart rate during infusion of PGE1 into the animals treated with AgentitR or reserpine. In dogs receiving continuous infusions of PGE1 in doses lowering the blood pressure, infusions of noradrenaline or adrenaline still induced a marked rise in blood pressure. Infusion of the sympathetic ganglionic stimulating agent DMPP or electrical stimulation of the central ends of the cut vagus nerves also raised the blood pressure in dogs receiving PGE1 The hypothesis was discussed that PGE1 lowers the blood pressure by actions independent of catecholamines.
Chemically pure prostaglandin E was infused in doses of 0.2–4.7 μglkglrnin in two healthy male subjects over periods of 4–10 min. Tachycardia, reddening of the faoe, headache and an oppressive feeling in the chest were noted. Systemic arterial blood pressure and cardiac output fell moderately.
Accuracy of two systems—conventional (DRF 400, Diasonics) and colorcoded (Angiodynograph, Quantum/Phillips) image-directed Doppler ultrasonography—was investigated using an in vitro model that generated both monophasic and triphasic pulsatile flow patterns. Estimated and actual blood volume flow rates showed good correlations, but the sampling with a hand-held transducer led to wide variations in measurement error for the conventional (−69.2% to 50%) and the colorcoded (−79.3% to 265.7%) systems. By performing multiple measurements, one could improve accuracy considering only the maximal values of a series instead of the mean values. Accuracy was impaired by interposed muscular or fatty tissue due to false low time-average velocity measurements caused by a loss of Doppler signal. Comparison of both systems revealed significant differences between pulsatility index values (p < 0.001), blood flow velocities (p < 0.001), and blood volume flow rates (p < 0.05 for program flow, p < 0.001 for manual and automatic flow program of the color-coded system).
The effects of the prostaglandins PGE1 and PGE2 on the deformability of the human erythrocyte were studied using spin-labeled erythrocytes. Two magnetic resonance parameters were measured: (1) The orientation relaxation time, , for the erythrocyte, and (2) the order parameter, S, for a fatty acid spin label bound to the membrane. Prostaglandins PGE1 and PGE2 exhibited opposite effects on both and S. PGE2 made the cell less deformable (increases of and S) and PGE1 made the erythrocyte more deformable (decrease of and S).
In vasospastic diseases, vasodilator drugs that act upon the sympathetic nervous system may have a beneficial effect in many patients by increasing cutaneous capillary blood flow. These agents may decrease persistent vasospasm or the number and intensity of attacks in Raynaud's phenomenon but usually do not produce complete relief. Full benefit is often prevented by unpleasant and sometimes severe side effects that limit dosage. Reserpine or guanethidine is the drug of choice; tolazoline long-acting tablets are added when further relief is needed. Papaverine, niacin, isoxsuprine and cyclandelate are representative of vasodilator drugs that directly relax vascular smooth muscle. When administered by mouth, these drugs are not potent peripheral vasodilators, and it may be concluded that they are not of value in the treatment of peripheral vascular diseases. Review of the clinical studies of vasodilator drugs in obstructive vascular disease reveals little substantive evidence to support their use. They are not effective in the treatment of either intermittent claudication or ischemic symptoms or signs at rest. They fail to increase blood flow in most patients with ischemic limbs, even when administered locally by the intra-arterial route. No drug has been shown to increase muscle blood flow during exercise when patients with intermittent claudication experience symptoms.
Acute vasodilatation was produced by infusion of prostaglandin E1 (PGE1) in the femoral artery in 6 patients with occlusive arterial disease of the legs and in 3 normal subjects. The effect on blood flow and on blood pressure was measured at different segments of the leg with the strain gauge technique, isotope clearance technique, and photoelectric technique. Skin temperature was measured at different levels by using thermocouples. The blood pressure on the legs decreased at all segments during vasodilatation as well in patients as in controls. The blood flow increased in all segments in normal controls. In patients the blood flow increased proximally in the legs. Distally, however, no increase could be demonstrated. As a good effect of PGE1, on ischaemic rest pains has been reported, mechanisms other than vasodilatation should probably be considered.
To investigate the in vivo whole blood metabolic clearance rates and sites of metabolism of prostaglandins A1 and E1 in man, constant infusions of the tritiated compounds were administered to normal subjects and to patients undergoing cardiac catheterization. The whole blood metabolic clearance rate of [3H]prostaglandin A1 in eight men was 5,003 +/- 864 liters/day (SD) or 2,546 +/- 513 liters/day per m2 (SD). Nonradioactive prostaglandin A1 was similarly infused in two subjects, and the metabolic clearance rates were determined, utilizing a specific radioimmunoassay. The clearance rates with this method correlated closely with those determined by the isotope infusions. Extraction studies of prostaglandin A1 showed that pulmonary, splanchnic, renal, and extremity perfusions resulted in 8.1 +/- 4.1, 56.1 +/- 10.1, 50.3 +/- 3.4, and 34.4 +/- 5.9% (SEM) removal, respectively. With [3H]=prostaglandin E1, the whole blood metabolic clearance rate was determined from the pulmonary artery concentration in three patients and averaged 4,832 +/- 1,518 liters/day (SD) or 2,686 +/- 654 liters/day per m2 (SD). Pulmonary extraction was 67.8 +/- 6.8% (SEM) and extremity removal averaged 6.6 +/- 4.9% (SEM). These results indicate that A prostaglandins are metabolized by several organs, such as the liver and kidney, and possibly by intravascular pathways as well. In man, the E prostaglandins are primarily metabolized by the lung, but extraction is not complete and approximately one-third may escape lung metabolism. Thus, these findings suggest that both E and A prostaglandins in the venous circulation may reach the systemic circulation in man.
The intraarterial and intravenous infusion of prostaglandin E1 (PGE1) today is well established in the therapy of peripheral arterial occlusive disease. This review summarizes the results of pharmacological-clinical studies and the influence of PGE1 on the pathomechanism of ischaemia due to its antithrombotic, leukocyte and endothelial stabilizing properties. Clinical data available on continuous and intermittent infusion for both modes of administration are critically appraised, taking into account more recent data on active metabolites.
This study investigates the effects of 13,14-Dihydro-PGE1 (PGE0) in comparison to PGE1 on human platelets, human polymorphonuclear granulocytes (PMN) and a number of vessel preparations of different species. The potency of PGE0 in inhibition of platelet and neutrophil activation is similar to PGE1. The vascular action differs. At a comparable molar potency, PGE0 showed stronger contractile and less relaxing effects than PGE1. The biological activities of PGE0 may contribute to the in vivo effects of PGE1 in treatment of peripheral arterial occlusive disease, in particular at high-dose i.v. administration.
We have demonstrated recently the formation of a biologically active metabolite of prostaglandin (PG) E1, 13,14-dihydro-PGE1, during intravenous infusions of PGE1 in patients with peripheral arterial occlusive disease. We have now investigated the levels of the immediate precursor of 13,14-dihydro-PGE1, the biologically inactive 15-keto-13,14-dihydro-PGE1, during intravenous administration of 20 micrograms, 40 micrograms or 80 micrograms PGE1 over a period of 60 min to human volunteers. It was found that levels of 15-keto-13,14-dihydro-PGE1, but not those of PGE1 itself, increased in a dose-dependent manner. Thus, increased formation of 13,14-dihydro-PGE1 from 15-keto-13,14-dihydro-PGE1 with increasing doses of PGE1 can be expected to occur. It remains to be investigated, to which extent formation of small amounts of 13,14-dihydro-PGE1 during intravenous infusion of PGE1 could contribute to the therapeutic effects of PGE1 in patients with peripheral arterial occlusive disease.
Prostaglandin E1 is offered as a new therapeutic agent in the treatment of severe peripheral arterial occlusive disease. Especially when treating patients with ulcers or gangrene, the oxygen tension of the skin should improve during PGE1 administration. The new technique of assessing skin surface oxygen pressure histograms allows study of the skin microcirculation in vivo. Oxygen histograms were determined on the forefeet of 19 patients with different degrees of disease and different occlusion levels before and during a single intraarterial infusion of PGE1 at a dosage of 1.5 ng/kg body weight/min. Only 9 patients showed improvement during the infusion period. Skin oxygen pressure was increased to a large extent only in patients assumed to suffer from diabetic microangiopathy. The effect of a long-term therapy with PGE1 on skin microcirculation remains to be settled.
The purpose of this study was to compare the haemodynamic effects of intra-arterial and intravenous prostaglandin E1 (PGE1) both injected and infused into ischaemic legs. Continuous intra-arterial infusion of PGE1 induced a significantly greater increase in skin temperature and blood flow than did intravenous drip infusion. Furthermore, intra-arterial infusion caused no steal phenomenon in the toe as indicated by skin temperature. On the other hand, toe skin temperature decreased during intravenous drip in 33 per cent of the legs tested. Continuous intravenous infusion also produced a significantly greater increase in toe skin temperature than did brief intravenous drip. In three of ten ulcers healed by continuous intra-arterial infusion, no definitive effect was obtained from continuous intravenous infusion even when it was repeated up to three times before continuous intra-arterial infusion. Intra-arterial injection of PGE1 caused no significant increase in toe skin temperature.
Increasing doses of prostaglandin E1 given intravenously do not influence the hemodynamic parameters up to a dosage of 1500 ng/min. Intra-arterial administration of a mixture of nucleotides and nucleosides in therapeutic doses induces an increase in the blood flow volume at rest of up to 400%. With dosages of 20 ng/min and more, intra-arterial administration of PGE1 induces only a slight increase in the blood flow volume of the extremity under treatment. The therapeutic effects of the substance, therefore, are probably more due to other mechanisms of action than to hemodynamic effects.
The clinical value of isotopic measurement of blood flow in the calf muscles and blood pressure in the skin is compared to that of other methods for measurement of flow and pressure distal to arterial occlusion. Surgical and medical therapy is discussed in the light of such physiologic measurements.
The pathway in the metabolism of prostaglandins E1 in kidney, spleen and liver from swine is 1) oxidation of the 15-hydroxyl group to a ketone, 2) reduction of the Δ13-double bond and partly 3) stereospecific reduction of the 15-keto group to dihydro-prostaglandin E1 (15 S).
Prostaglandin E1 (PGE1) has been used clinically in the treatment of ischemic peripheral vascular disease. However, the preferred route of administration and its influence on the distribution of blood flow to the skin, muscle, bone, and arteriovenous anastomoses ( AVAs ) have yet to be established. Bilateral femoral arterial blood flow was measured electromagnetically in 10 anesthetized adult mongrel dogs (mean weight 16.5 kg). The distribution of femoral arterial flow to the skin, muscle, bone, and AVAs was determined with use of femoral intra-arterial injections of radioactively tagged microspheres (15 +/- 1 mu) before, during, and 1 hour after 20 minutes of intravenous and intra-arterial infusions of PGE1 at 0.1 microgram kg-1 min-1. Intra-arterial infusions caused a significant (P less than 0.003) increase in femoral arterial flow (462 +/- 58 ml X min-1), which was sustained throughout the infusion. The distribution of flow to the skin increased significantly (P less than 0.01) to 24.1 +/- 2.1%, whereas that through AVAs was significantly (P less than 0.05) decreased to 3.2 +/- 0.9%. Femoral arterial blood flow did not change during intravenous infusions; however, there was a significant (P less than 0.01) reduction in the distribution to muscle (41.1 +/- 10.5%) associated with a significant (P less than 0.02) increase in distribution through AVAs (30.8 +/- 11.5%). These data demonstrate the superiority of intra-arterial infusion over intravenous infusions of PGE1 in the canine hindlimb. There was a significant increase in femoral arterial blood flow with increased distribution to the skin and decreased shunting. Femoral arterial blood flow did not change during intravenous infusions; however, a reduction in the distribution of flow to the muscle was accompanied by an increase in shunting.
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