Rapid Bolus Injection Research Articles

Phase I Clinical and Pharmacokinetic Study of LU103793 (Cemadotin Hydrochloride) as an Intravenous Bolus Injection in Patients with Metastatic Solid Tumors

<i>Background:</i> To study the toxicity and pharmacokinetics of LU103793 (Cematodin®), a novel cytotoxic anticancer drug being an analogue of Dolastin 15 which was isolated originally from the Indian Ocean sea hare Dolabella auricularia. <i>Method:</i> 9 patients with refractory metastatic solid tumors were treated in a phase I study. The drug was administered as rapid (5 min) intravenous bolus injection at 3-weekly intervals. 14 courses of LU103793 were totally administered. The starting dose was 2.5 mg/m2 and escalated to 20 mg/m2 within 4 steps. <i>Results:</i> The dose-limiting toxicity was a) reversible hypertension, and b) cardiac infarction. No significant myelotoxicity was observed. Other toxicities were nausea and vomiting, drug fever, pain at the tumor site and asthenia. Concentrations of LU103793 and its main metabolite were measured in all 9 patients in whole blood samples. Two exponential terms are necessary to describe the c(t) profile. The pharmacokinetic parameters at 20 mg/m² are: maximum concentration 9.0 ± 7.2 μ<i>M</i>, the area under the curve 37.3 ± 6.8 μ<i>M</i> × h, the plasma clearance 0.8+0.14 1/hour/m², the volume of distribution at steady state 9.6 ± 2.0 1/m² and the elimination half-life 10.3 ± 1.5 h. The AUC was increasing from 4.6 μ<i>M</i> × h at 2.5 mg/m² dose level to 37.3 μ<i>M</i> x h at 20 mg/m² dose level, suggesting a linear kinetic in the range of the tested doses. No objective tumor regression was observed. Conclusions: The dose-limiting toxicity (DLT) was reached at 20 mg/m² with cardiovascular side-effects. Hypertension and a myocardial infarction determined the DLT. The mechanism of the observed cardiovascular side effect is still unclear. In case that high peak blood levels are critical with respect to the observed toxicity, prolongation of the drug administration either as continuous infusion or a split mode (repetitive drug application over 3-5 days) should avoid this problem. Phase I trials with such application modes are in progress.

Contrast-enhanced magnetic resonance tomoangiography: A new imaging technique for studying thoracic great vessels

The authors propose a new imaging approach for studying thoracic great vessels, using high-speed MR imaging combined with intravenous rapid bolus injection of a paramagnetic contrast media. The decrease of the T 1 relaxation time of flowing blood induced by the contrast agent (Gd-DOTA) caused an increased signal intensity within the vessel lumen for a time period allowing multiplanar imaging of various vascular structures. The intraluminal signal enhancement is mainly related to the blood concentration of the contrast agent as in conventional X-ray angiography. Information on the aorta and pulmonary arteries obtained by the so-called contrast-enhanced magnetic resonance tomoangiography appears complementary to that obtained with other vascular MR imaging procedures such as cine-MRI and magnetic resonance angiography (MRA).

Effectiveness and safety of a single intravenous Bolus injection of tissue-type plasminogen activator in acute myocardial infarction

The efficacy of multiple intravenous bolus injections of tissue-type plasminogen activator (t-PA) in inducing rapid coronary recanalization in patients with acute myocardial infarction was previously demonstrated. In this Bolus Dose-Escalation Study of Tissue-Type Plasminogen Activator (BEST), the efficacy of 3 different doses of a single rapid intravenous bolus injection of t-PA (duteplase, Wellcome Foundation, London) in inducing coronary patency (Thrombolysis In Myocardial Infarction perfusion grade 2 or 3) in 64 patients with acute myocardial infarction presenting <6 hours after onset of symptoms was investigated. At 60 minutes after administration of t-PA, the infarct-related coronary artery was patent in 9 of 17 patients (53%; 95% confidence interval [CI] 28 to 77%) after 0.3 MU/kg, in 14 of 23 (61%; 95% CI 39 to 80%) after 0.45 MU/kg and in 10 of 14 (71%; 95% CI 42 to 92%) after 0.6 MU/kg. At 90 minutes after t-PA, coronary patency was present in 9 of 17 cases (53%; 95% CI 28 to 77%) after 0.3 MU/kg, in 12 of 24 (50%; 95% CI 29 to 71%) after 0.45 MU/kg and in 10 of 13 (77%; 95% CI 46 to 95%) after 0.6 MU/kg. One patient in each dose group had a silent reoccluded infarct-related artery by 24 hours, and there were 2 clinical reinfarctions before discharge. No major bleeding events were observed. There were 5 hospital deaths, all unrelated to t-PA. A single intravenous bolus injection of 0.6 MU/kg of t-PA appears to be effective in inducing rapid coronary patency and to be safe in patients with acute myocardial infarction.

COMT inhibition with nitecapone does not affect the tyramine pressor response.

Nitecapone (OR-462) is a new selective COMT inhibitor with gastroprotective properties. The aim of the present study was to determine whether nitecapone potentiates the haemodynamic effects of a tyramine-induced increase in catecholamine release. The systolic blood pressure response to tyramine was studied in 11 healthy male volunteers (age 20-32 years). Tyramine was given i.v. as rapid bolus injections in increasing doses without drug intake and after oral intake of single doses of 25 mg and 100 mg of nitecapone. The tyramine dose required to increase systolic blood pressure by 30 mm Hg ('pressor dose') was 4.98 mg, 5.04 mg and 4.88 mg after no medication, and with 25 mg and 100 mg of nitecapone, respectively. There were also no differences in the systolic blood pressure response vs time curves between the three regimens. COMT inhibition with nitecapone did not potentiate the haemodynamic responses to tyramine-induced catecholamine release.

Disposition of gamma-glutamyl levodopa (gludopa) after intravenous bolus injection in healthy volunteers.

1. The pharmacokinetics of gludopa in healthy volunteers were studied at two doses, 250 micrograms kg-1 and 100 micrograms kg-1, after rapid intravenous bolus injection. 2. Gludopa had a clearance of 4.43 +/- 1.50 ml min-1 kg-1 and 4.92 ml min-1 kg-1 at the higher and lower doses, respectively. Corresponding half-lives were 29.2 +/- 3.7 min and 32.5 +/- 5.6 min, and volumes of distribution were 0.183 +/- 0.052 l kg-1 and 0.235 +/- 0.07/ l kg-1. 3. Urinary excretion of dopamine rose sharply after injection of gludopa at both doses, peaking at 30 min. At this time, amounts were over 215 and 60 times baseline values at the higher and lower dose of gludopa, respectively. Urinary dopamine rose in parallel with urinary levodopa excretion, supporting the view that levodopa is the precursor of urinary dopamine. 4. Less than 1% of the injected dose of gludopa was excreted unchanged in the urine. 5. These findings suggest that, in man, gludopa is an efficient pro-drug for dopamine. Gludopa may find therapeutic use in conditions where the beneficial renal effects of dopamine may be indicated.

Computed Tomography and Acute Pancreatitis

Computed tomography (CT) is the best overall imaging modality in the clinical management of acute pancreatitis. It can detect complications such as phlegmonous extension outside the gland, abscess and pseudocyst formation, and hemorrhage. Pancreatic necrosis can be diagnosed with the use of dynamic CT scanning after the rapid bolus injection of iodinated contrast media. The information gathered can be used to guide clinical management and provide anatomic detail for percutaneous aspiration and drainage or surgical intervention when indicated.

Effects of central bolus injections of potassium chloride on arterial potassium concentration in patients undergoing cardiopulmona0ry bypass

The effects of central venous bolus injections of potassium chloride (KCI) on arterial potassium concentration were studied in patients undergoing cardiopulmonary bypass. Ten subjects were studied, and each received a rapid bolus injection of KCI, 33 μEq/kg, both before and after cardiopulmonary bypass. Injections were delivered through the proximal infusion port of a 7.5F pulmonary artery catheter, which was situated in either the superior vena cava or the right atrium. Monitored variables included the electrocardiogram, mean arterial, central venous, and pulmonary artery pressures, end-tidal carbon dioxide and inspired oxygen concentrations, and temperature. Blood was sampled continuously at either the radial artery alone or both the radial artery and aortic root at 2 mL/4.3 s. The difference in magnitude between the maximal potassium concentration achieved and the prebolus baseline potassium concentration (delta K) was correlated with cardiac output, stroke volume, and prebolus baseline potassium concentration (baseline [K +]), using simple linear regression analysis. Although significant hyperkalemia leg, 7 to 9 mEq/L) developed in both the aortic root and radial artery, this was of no electrocardiographic or hemodynamic consequence, presumably because of the transient nature of the hyperkalemic response, following bolus injection of KCl. There was no significant correlation between delta K and cardiac output or stroke volume; however, delta K did correlate significantly with the Baseline [K +] in a direct linear relationship. It is concluded that central bolus injections of KCI through the proximal infusion port of the pulmonary artery catheter at 33 μEq/kg are safe. This technique should be used cautiously in patients with extremely low cardiac outputs or where intracardiac shunting of blood may exist, as these situations could potentially result in greater hyperkalemic responses than those observed in the current study.

Effect of Rate of Injection on the Neuromuscular Block Produced by Vecuronium

A subparalytic dose (0.015 mg/kg) of vecuronium bromide was administered to matched pairs of patients undergoing routine dental surgery under enflurane-nitrous oxide/oxygen anesthesia either as a rapid bolus injection or as a slow infusion over 5 min. It was demonstrated that bolus injection produced peak plasma levels of drug considerably greater than those following slow infusion. Time to maximum block was more rapid following bolus (368 +/- 84 [SD] sec) than by infusion (615 +/- 88 sec), but the maximum block produced, either demonstrated by the reduction in amplitude of T1 from control or the T1:T4 ratio on the integrated electromyogram (Datex IEMG), was similar in each group irrespective of rate of injection, T1 and T4 referring to the first and last twitch in a train of four series.

Dynamische MR-Tomographie intrahepatischer Tumoren

By combining rapid imaging and bolus injections of the paramagnetic contrast medium gadolinium-DTPA, it is possible to perform dynamic MR imaging. The diagnostic value of dynamic MR imaging was investigated in 28 patients with focal liver lesions. Malignant tumours appear hypo-intense during the early phase of the dynamic study and are better distinguished from normal liver tissue. Haemangiomas produce a typical 'fill-in phenomenon' after contrast application and achieve very high signal intensity. Focal nodular hyperplasia is characterised by very rapid signal enhancement within the first minute after contrast injection. Dynamic MR imaging represents further improvement in the MR differentiation of liver tumours.

Alteration of hepatic tissue spaces by platelet-activating factor and phenylephrine.

Mean transit times for the movement of extracellular and intracellular reference compounds through isolated perfused rat livers were determined during exposure of livers to platelet-activating factor (AGEPC; 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine) and the alpha-adrenergic agonist phenylephrine, using the multiple indicator dilution technique. From the outflow profiles of rapid bolus injections of 3H-sucrose and 14C-urea given to the liver, the estimated intracellular volume of distribution of small freely permeant substances, Vi, and the ratio of intracellular to extracellular space, were computed. Exposure of the liver to AGEPC decreased Vi and by 32 and 34%, respectively, from control values, whereas infusion of phenylephrine increased Vi by 16% and by 33%. The results indicate that the hemodynamic effects of AGEPC in perfused rat liver cause the apparent loss of tissue space accessible to small permeant compounds. Phenylephrine, although increasing hepatic vascular resistance, measured at the portal vein, by the same magnitude as AGEPC, led to an increase in the apparent tissue space accessible to this same species.

Electrophysiological properties of paraventriculo-spinal neurones in the rat

In rats anaesthetised with urethane, electrical stimulation of the thoracic cord at T 9–10 evoked antidromic responses in neurons in the parvocellular portion of the ipsilateral paraventricular nucleus. Estimated conduction velocities in the spinally-projecting axons ranged from 0.6–5.9 m/sec. The majority (97%) of spinally projecting neurones were quiescent. Increases or decreases in the level of baroreceptor stimulation produced by intravenous injection of phenylephrine (1–5 μg) or sodium nitroprusside (10–15 μg) inhibited and excited amino acid-induced activity in5/8 and4/11 neurones respectively. Stimulation of vagal afferent endings by rapid bolus injection of 5-HT, to evoke the Bezold-Jarisch reflex, inhibited amino acid-induced activity in15/18 cells. Activation of gastric vagal afferents by distension of the stomach had no effect on paraventriculo-spinal cells. It is suggested that at rest the excitability of paraventriculo-spinal neurons is depressed by a tonic inhibitory input which arises from vagal afferent fibres in the heart.

Hepatic perfusion index in cirrhotic livers—investigation of imaging and analytical procedures

Dynamic hepatic scintigraphy was performed in a group of cirrhotic patients to evaluate the optimum imaging and analytical procedures necessary for the measurement of the hepatic perfusion index (HPI). Patients were studied in the posterior (n = 19) and the anterior (n = 14), positions, with either 0.2 or 0.5 ml of 99Tcm sulphur colloid administered as a rapid bolus injection. In each subject, three ROIs (small, medium and large) were drawn over the liver, and time-activity perfusion curves were generated. Analytical techniques were developed to allow flexibility in selecting the arterial and portal venous phases of the liver perfusion curve. The quality of the bolus, expressed as the full width at half-maximum of the left ventricular time--activity curve, was independent of the bolus volumes and patient positioning. The dispersion in the data and the inter-observer variation were less in the anterior view using medium and large ROIs, compared with the anterior small ROI and all the posterior ROI sizes. A time delay between liver and kidney arterial phases, if ignored, produced statistically significant effects on the values of the HPI. We conclude that HPI investigations are best performed in the anterior projection. Data analysis using a large liver ROI is preferred, and flexible data-processing techniques are recommended, particularly in the presence of a liver and kidney arterial time delay.

Dynamic Computed Tomography and Its Application to Ophthalmology

In this review of 31 patients, dynamic CT is discussed as a valuable tool in the study of the dynamics of blood flow in patients with unexplained visual problems that may be related to ischemic optic neuropathy. Dynamic CT scans are obtained by rapid-sequence CT imaging during and following a rapid bolus injection of intravenous contrast medium. It demonstrates the initial passage of contrast material through the area of interest, thus giving a true picture of the degree of vascularity and the dynamics of blood flow.

Role of the vagus in modulation by Ca2+ of the depressant action of adenosine and adenosine 5'-triphosphate on the canine sinus node in vivo.

1 The effect of elevated plasma Ca2+ level on the depressant action of adenosine and adenosine 5'-triphosphate (ATP) on the sinus node was studied in a canine model in vivo. 2 Under baseline conditions, both adenosine and ATP (3 mumol/kg) administered as a rapid bolus injection into the right atrium, caused a transient (less than 120 s) prolongation of sinus cycle length (SCL) of 128 +/- 25 ms and 439 +/- 31 ms respectively (P less than 0.02). 3 Infusion of CaCl2 (0.025 mmol/kg/min for 40 min) prolonged SCL from 257 +/- 17 ms to 418 +/- 17 ms (at t = 40 min; P less than 0.05), but did not significantly change arterial blood pressure. 4 Ca2+ infusion had no significant effect on SCL prolongation caused by adenosine (128 +/- 25 ms vs 151 +/- 31 ms; before and at t = 40 min respectively), but caused pronounced enhancement of SCL prolongation caused by ATP (439 +/- 31 ms vs 1215 +/- 401 ms; before and at t = 40, respectively, P less than 0.02). 5 Atropine (0.2 mg/kg, i.v.) did not affect the action of adenosine before or during Ca2+ infusion. In contrast, atropine abolished SCL prolongation by Ca2+ and abolished Ca2+ enhancement of the action of ATP. 6 The present data give further support to the hypotheses that (a) calcium potentiates vagally mediated actions and (b) the vagus is involved in the differential electrophysiological actions of adenosine and ATP in the canine heart in vivo.

Perfusion of colorectal hepatic metastases. Relative distribution of flow from the hepatic artery and portal vein.

The importance of portal circulation in the delivery of drugs and nutrients to colorectal hepatic metastases is controversial. Using 13N (nitrogen 13) amino acids and ammonia with dynamic gamma camera imaging, we demonstrate, for the first time in human beings, a quantitative advantage of hepatic artery compared with portal vein infusion. Eleven patients were studied by hepatic artery injection, five patients were studied by portal vein injection, and two patients had injections through both routes. Data collected from the liver for 10 minutes after rapid bolus injection of 13N L-glutamate, L-glutamine, or ammonia were compared with 99mTc (technetium) macroaggregated albumin (MAA) images produced after injection through the hepatic artery or portal vein at the same session. Tumor regions defined from 99mTc sulfur colloid scans were compared with nearby liver areas of similar thickness. For the 13N compounds, the area-normalized count rate at first pass maximum (Qmax) and the tissue extraction efficiency were computed. The tumor/liver Qmax ratios for MAA and 13N compounds were highly correlated. Both tumor and liver extracted more than 70% of the nitrogenous compounds. The tumor/liver Qmax ratios reflect the relative delivery of injected tracer per unit volume of tissue. After hepatic artery injection the Qmax ratio was 1.03 +/- 0.33 (mean +/- SD), significantly exceeding the Qmax ratio of 0.50 +/- 0.34 after portal vein injection (P less than 0.003). Therefore, more than twice as much of a nutrient substrate is delivered per volume of tumor relative to liver by the hepatic artery as by the portal vein; the high extraction efficiency demonstrates that the hepatic artery flow is nutritive; and the delivery of substance in solution (such as nutrients or drugs) to tumor and liver tissue correlates with the distribution of colloids such as macroaggregated albumin after hepatic arterial and portal venous injection.

DIAGNOSIS OF COMMON CONGENITAL HEART ANOMALIES IN THE DOG USING SURVEY AND NONSELECTIVE CONTRAST RADIOGRAPHY

The most common canine congenital heart anomalies include patient ductus arteriosus, ventricular septal defects, tetralogy of Fallot, pulmonic stenosis, and aortic stenosis. Survey radiography and nonselective (venous) angiography can allow the practicing veterinarian to confirm the diagnosis in many of these patients. Typical radiographic findings using these diagnostic procedures are reviewed. Nonselective angiocardiography is a relatively easy, rapid, and noninvasive procedure which can be performed using conventional equipment. The major disadvantage of this special procedure is that the superimposition of opacified structures can make the identification of some left‐to‐right shunts difficult. Dilution of contrast medium can occur if a rapid bolus injection is not made.

Intravenous isosorbide dinitrate infusion in the management of unstable angina pectoris refractory to conventional medical therapy.

During the past 2 years, 102 patients were treated for unstable angina pectoris (AP) in our department. Fifteen of them had recurrent chest pain at rest despite treatment with various anti-anginal agents, or prolonged chest pain unresponsive to sublingual nitroglycerin; they received intravenous isosorbide dinitrate (ISDN) infusion. A rapid bolus injection of 2 to 6 mg followed by an infusion of 2 to 5 mg/hr was given to 10 patients with acute chest pain, and 5 patients, who were free of chest pain at the time, but had repeated episodes of angina in the past 24 hours, were given ISDN infusion without a bolus injection. Chest pain disappeared completely in 13 patients, but recurred in 2 of them when the dose was tapered. Two other patients experienced recurrent chest pain during ISDN infusion, and additional boluses were given. The hospital course was uneventful in 11 patients. Four patients who had recurrent anginal attacks underwent emergency coronary cineangiography under intraaortic ballon counterpulsation and aorto-coronary bypass surgery. There were no hospital deaths, no one had subsequent acute myocardial infarctions, and only 2 patients had mild to moderate headache as a side effect. Although the patient population is small, intravenous ISDN infusion is useful in the management of severe unstable AP.

Evaluation of renal functional image using Tc-99m DTPA.

Functional Image (FI), which represents dynamic local renal function in one image, has been made possible only by digital image processing. The first FT obtained by rapid bolus injection of the radiolabeled medium is considered to be useful for evaluation of initial local renal blood flow. FT has the advantage that it can be performed simultaneously with conventional rou-tine examinations of the renal function.

Paraganglioma of the Heart: The Value of Magnetic Resonance Imaging in the Preoperative Evaluation

Although the 131I-metaiodobenzylguanidine scan has proven reliable in identifying mediastinal paragangliomas, further localization has usually required dynamic computerized tomographic scanning which requires rapid bolus injection of contrast material. In the case presented herein, magnetic resonance imaging provided accurate preoperative localization and added important anatomic detail that was not appreciated with dynamic computerized tomograms or with other studies. Magnetic resonance imaging can accurately localize cardiac paragangliomas without injection of contrast material and may provide more detailed information for better guidance for surgical excision.

Tissue distribution and myelotoxicity of daunomycin in the rat: Rapid bolus injection vs continuous infusion

The pharmacokinetic and cytotoxic behaviour of daunomycin in rats (7.5 mg/kg) when administered as an i.v. bolus injection were compared with those of a 3- hr infusion. After an i.v. bolus injection, the plasma drug levels decreased triphasically ( t 1 2α = 0.8 min , t 1 2β = 29.6 min and t 1 2γ = 9.9 hr ). The organs showed two types of concentration/time curves. One was found in the lungs, liver, kidneys and heart and had an initial high drug concentration followed by a relatively rapid elimination. The other was shown by the hemopoietic tissues (spleen and bone marrow): the drug uptake phase lasted longer (about 1.5 hr) and the elimination was slower. In general, daunomycin infusion led to substantially lower plasma and tissue levels, including in the heart, liver and kidneys. Again the hemopoietic tissues behaved in a different way: in spleen and bone marrow almost equal drug levels were obtained after daunomycin infusion as compared to a bolus injection. The myelotoxicity after daunomycin treatment was assessed by CFU-S (colony forming units-spleen) survival: the bolus injection killed as many CFU-S as did infusion (mean ± S.D: 11.8 ± 5.3 CFU-S survival versus mean ± S.D.: 13.5 ± 2.4). Thus, it can be predicted that daunomycin infusion will lead to less cardiotoxicity but to an equal bone marrow suppression.