[Effect of intravenous infusion of polyosm preparation on diuresis and indices of systemic and cerebral hemodynamics].
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Administration of indomethacin may aid treatment of intracranial hypertension, and the present study was conducted to determine the optimal dose. In healthy volunteers, cerebral blood flow (CBF) has been shown to decrease considerably after a bolus dose of indomethacin, 0.4 mg/kg, followed by continuous infusion, 0.4 mg/kg/h. This decrease was sustained for 6 h without any evidence of adaptation. In a randomized study in healthy volunteers, indomethacin, 0.1, 0.2 and 0.3 mg/kg, was given as bolus, followed by continuous infusion of 0.1, 0.2 and 0.3 mg/kg/h. CBF decreased from normal levels (52-74 ml/100 mg/min) to 38-51 ml/100 g/min. There were no differences among the three groups in CBF reduction, and the reduction was sustained during the 6-h infusion period. Rectal application of 100 mg indomethacin was found to reduce CBF from normal levels (54-74 ml/100 mg/min) to 33-48 ml/100 mg/min. These low levels were only sustained for 2 h, and values returned to normal over the next 6 h. We observed no rebound phenomenon 2 h after stopping the infusion and no rebound after 100 mg of rectally applied indomethacin. Since a dose as low as 0.1 mg/kg/h is effective, it is possible to treat most patient in a 24-h schedule without going over maximum recommended doses.
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The camptothecins are a class of potent cytotoxic anticancer agents that interact with the nuclear enzyme topoisomerase I to produce lethal DNA strand cleavages. 9-Amino-20(S)-camptothecin (9AC) was introduced into Phase I clinical trials in dimethylacetamide and polyethylene glycol 400 in a 10 mM phosphoric acid vehicle for i.v. solubility. A lyophilized colloidal dispersion (CD) of 9AC for reconstitution with 20% dextrose in normal saline was developed as an alternative formulation. Patients (ages 25-75 years) with normal liver and kidney function, Eastern Cooperative Oncology Group performance status < or = 2, and up to two prior chemotherapy regimens were treated. The initial infusion rate was 37.5 micrograms/m2/h as a 72-h continuous infusion (2.7 mg/m2 total dose). Patient cohorts were treated with escalating infusion rates until grade 4 hematological or other grade 3 toxicity developed. Pharmacokinetic sampling was performed on all patients, and 9AC lactone concentrations in plasma were determined by a high-performance liquid chromatographic assay. Twenty-five patients received a total of 65 courses of 9AC CD at doses from 2.70 to 4.65 mg/m2. The dose-limiting toxicity was neutropenia, with little nonhematological toxicity. Nonlinear regression analysis of pooled patient data yielded a total plasma clearance of 30.3 +/- 4.5 liters/h/m2, a half-life of 22.5 +/- 8.5 h, a mean residence time of 9.7 +/- 3.5 h, and a steady-state volume of distribution of 325 +/- 145 liters/m2. Although no objective responses were seen, 9 of 25 patients exhibited stable disease for 2-6 months. The plasma pharmacokinetics of 9AC lactone in cancer patients were comparable between the 9AC CD and soluble formulations. The dosing regimen recommended for Phase II trials of the 9AC CD formulation is 54.2 micrograms/m2/h, given as a 72-h continuous i.v. infusion every 3 weeks.
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3,4-Dihydro-2-amino-6-methyl-4-oxo-5-(4-pyridylthio)-quinazolon e dihydrochloride (AG337) is a nonclassical inhibitor of thymidylate synthase (TS) designed to avoid potential resistance mechanisms that can limit the activity of classical antifolate antimetabolites. A clinical pharmacokinetic and pharmacodynamic study of AG337 given as a 24-h i.v. infusion was performed. Thirteen patients received 27 courses over the dose range 75-1350 mg/m2. Plasma AG337 concentrations were achieved which, in preclinical models, were associated with antitumor effects. AG337 clearance was saturable, and the pharmacokinetics of the drug at doses above 300 mg/m2 was best described by a one-compartment model with saturable elimination (median Km = 6.5 microgram/ml; range, 4.1-13 microgram/ml; median Vmax = 2.0 microgram/ml/h/m2; range, 0.96-5.6 microgram/ml/h/m2). Following the end of the infusion, AG337 was cleared rapidly (t1/2, 53-193 min), and levels were less than 0.2 microgram/ml in all patients by 48 h. Plasma protein binding was 96-98%, and the urinary excretion of AG337 as unchanged drug did not exceed 30% of the dose administered. Measurements of plasma deoxyuridine (dUrd) concentrations showed that doses of 600 mg/m2 and above of AG337 produced a consistent elevation in plasma dUrd levels (60-290%), suggesting that TS inhibition was being achieved in patients. However, in all cases dUrd concentrations had returned to pretreatment levels 24 h after the end of the infusion, suggesting that TS inhibition was not maintained. Local toxicity, probably due to the infusate pH, was the only significant adverse effect observed. These studies have shown that cytotoxic AG337 plasma concentrations can be readily achieved without acute toxicity and that these concentrations are associated with elevations in plasma dUrd levels. The lack of prolonged dUrd elevations indicates that extended administration should be explored using central line or p.o. administration to avoid local toxicity.
In this paper, we have proposed a method for the dosage regimen evaluation of intrevenously infused drugs which obey first order clearance kinetics. An example of application is given.
BACKGROUND: Abnormal expression of Ras proteins frequently is found with oncogenic transformation making ras a promising therapeutic target. ISIS 2503 is a 20-base antisense phosphorothioate oligodeoxyribonucleotide that specifically downregulates H-ras expression and inhibits tumor cell growth in preclinical studies. Here, the authors report an initial clinical study of the safety and tolerability of an intravenous infusion of ISIS 2503 in patients with advanced cancer. METHODS: A continuous intravenous infusion of ISIS 2503 was administered for 14 days every 3 weeks to 23 patients with a variety of solid tumors refractory to standard therapy. The dose of ISIS 2503 was increased in sequential cohorts of patients, as toxicity allowed, until a final dose of 10.0 mg/kg/day of body weight was reached. Toxicity was scored by the National Cancer Institute's Common Toxicity Criteria, and tumor response was monitored after every two treatment cycles. Pharmacokinetic studies were performed in some of the patients up to, and including, the final dose of 10 mg/kg/day/day of body weight. Levels of H-ras mRNA expression also were determined in the circulating lymphocytes of some patients by quantitative reverse transcriptase-polymerase chain reaction. RESULTS: A total of 23 patients received 63 cycles of ISIS 2503 at escalating doses to 10.0 mg/kg/day without dose-limiting toxicity and only minimal side effects. Four patients had stabilization of their disease for 6-10 cycles. No consistent decreases in H-ras mRNA levels were observed in peripheral blood lymphocytes. CONCLUSIONS: ISIS 2503, an antisense oligonucleotide against H-ras, was well tolerated as a single agent at doses up to 10.0 mg/kg/day by 14-day continuous intravenous infusion. Several patients had stabilization of disease, suggesting that ISIS 2503 had some tumor growth inhibitory effects and future trials of ISIS 2503 in combination with chemotherapy should be considered.
Using a newly developed iontophoretic delivery device, a novel inotropic catecholamine, pharmacologically similar to dobutamine, has been successfully administered to dogs by noninvasive transdermal infusion for periods of up to 1.5 h. The technique was compared with intravenous infusion and shown to be capable of achieving the same degree of cardiac contractility and steady-state plasma concentrations of the inotrope. There was also a good linear relationship between the applied current and the resulting steady-state plasma concentrations of the inotrope. Approximately 2 mA of applied current during transdermal iontophoresis produced a response equivalent to an intravenous infusion of 1 micrograms/kg/min of the drug.
Almost all agents that exhibit neuroprotection when administered into the cerebral ventricles are ineffective or much less effective in rescuing damaged neurons when infused into the blood stream. Search for an intravenously infusible drug with a potent neuroprotective action is essential for the treatment of millions of patients suffering from acute brain diseases. Here, we report that postischemic intravenous infusion of a ginseng saponin, ginsenoside Rb(1) (gRb(1)) (C(54)H(92)O(23), molecular weight 1109.46) to stroke-prone spontaneously hypertensive rats with permanent occlusion of the middle cerebral artery distal to the striate branches significantly ameliorated ischemia-induced place navigation disability and caused an approximately 50% decrease in the volume of the cortical infarct lesion in comparison with vehicle-infused ischemic controls. In subsequent studies that focused on gRb(1)-induced expression of gene products responsible for neuronal death or survival, we showed that gRb(1) stimulated the expression of the mitochondrion-associated antiapoptotic factor Bcl-x(L) in vitro and in vivo. Moreover, we revealed that a Stat5 responsive element in the bcl-x promoter became active in response to gRb(1) treatment. Ginsenoside Rb(1) appears to be a promising agent not only for the treatment of cerebral stroke, but also for the treatment of other diseases involving activation of mitochondrial cell death signaling.
1. Rats received intravenous infusions of dopexamine, an agonist with selectivity for D1-dopamine receptors and beta 2-adrenoceptors (240 micrograms kg-1 h-1), isoprenaline, a beta 1- and beta 2-adrenoceptor agonist (40 micrograms kg-1 h-1) or vehicle (isotonic saline at pH 2.5) for 7 days via subcutaneously implanted osmotic minipumps. Tissues were then removed for determination of functional responsiveness to beta 1-adrenoceptor, beta 2-adrenoceptor and dopamine D1-receptor stimulation. 2. The beta 1-adrenoceptor-mediated responses of the spontaneously beating right atrium (increase in rate) and paced left atrium (increase in tension) showed significant reductions in sensitivity to isoprenaline following isoprenaline infusion. The EC50 values were significantly increased from 5.6 to 17.7 nM in right atria and from 7.4 to 27.1 nM in left atria. The maximum rate increase of right atria was also significantly less after isoprenaline infusion compared with controls (164.0 and 251.9 beats min-1, respectively) but the maximum tension responses of left atria were not significantly different. After infusion with dopexamine, however, there was no change in sensitivity of the left or right atria to beta 1-adrenoceptor stimulation by isoprenaline. 3. beta 2-Adrenoceptor-mediated relaxation responses to isoprenaline of the pulmonary artery, constricted with noradrenaline (6 x 10(-8) M), showed no significant difference in maximum response or EC50 in tissue from isoprenaline- or dopexamine-infused rats compared with vehicle-infused controls. beta 2-Adrenoceptor-mediated vasodilator responses were also examined in the kidney perfused with the thromboxane A2 analogue, U46619 (7.1 x 10(-8) M) to raise perfusion pressure. As with the pulmonary artery, there was no significant difference in ED50 or maximum response to isoprenaline in kidneys from isoprenaline infused animals compared with vehicle controls.4. The DI-receptor-mediated vasodilator responses to dopamine of the kidney perfused with U46619were reduced after infusion of rats with dopexamine. The maximum fall in perfusion pressure(16.0 mmHg) and ED50 value (5.2 microg) were significantly different from those after vehicle infusion(31.5 mmHg; 1.5 microg).5. These results show that functional responses mediated via beta1-adrenoceptors and DI-receptors are reduced by intravenous infusions of isoprenaline and dopexamine, respectively. In contrast, the beta2-adrenoceptor-mediated vasodilator responses of the pulmonary artery and kidney are not reduced by these agonists. Thus, under identical conditions, there appears to be selective down-regulation of peripheral beta 1- and D,-receptors, but not of beta 2-adrenoceptors.
The effect on cholesterol transport of an intravenous infusion of a fat emulsion (10%) Intralipid or 10% Lipovenös) in vivo was investigated in the rat. Intralipid (1.85 ml/hr/kg body weight in rts for 3 hr) caused a reduction (P < 0.05) in free cholesterol in the aorta (by 25%), in plasma high-density lipoproteins (64%) and in erythrocytes (11%) with a concomitant enrichment of liver free cholesterol (16%), suggesting an enhanced reverse cholesterol transport in this species. Lipovenös under the same conditions gave similar results. Our data support our previous in vivo study in man indicating that infusion of a fat emulsion is able even to remove cholesterol from the arterial wall and thereby possibly be considered as an antiatherosclerotic agent.
During the past decade, major advances have taken place with regard to intravenous infusion anaesthesia. New opioid analgesics, iv anaesthetics, and muscle relaxants have become available, which are characterized by a rapid onset of action, short duration of clinical effect, and favourable side effect profiles. Optimal administration of these drugs is often best achieved by continuous infusion, rather than a more traditional technique of intermittent bolus administration. New concepts in pharmacokinetic modelling also provide an enhanced appreciation of the factors which determine rates of recovery upon discontinuation of an intravenous infusion. Pharmacokinetic principles guide rational selection of the iv anaesthetic drugs according to both procedure and patient-specific requirements. In addition, improvements in the new programmable syringe infusion pumps provide a degree of simplicity and accuracy in operation, which make iv infusion of one, two or three components of the anaesthetic state a simple and practical reality for most procedures. In this CME article, these issues will be reviewed according to the following outline: Historical considerations; Rationale for continuous infusion of iv anaesthetic drugs; Pharmacokinetic and pharmacodynamic considerations; Infusion schemes; New techniques, new indications; IV anaesthetic delivery systems; Pharmacoeconomic considerations; Conclusions.
Glycine 1.5% was given by intravenous infusion at a rate of 50 mg/min over 20 min to 10 patients (aged 57-79 years) scheduled for transurethral prostatectomy. The concentrations of amino acids in serum and urine were measured at 0, 10, 20, 50, 80, and 140 min in the experiments in order to study how elderly men handle a glycine load. The results show an increase in the serum concentrations of alanine, proline, glutamine, glycine, serine, and threonine. The apparent distribution volume for the excess glycine was 33 +/- 9 L, the half-life was 41 +/- 7 min, and the total body clearance was 0.56 +/- 0.08 L/min, while the renal clearance for glycine was 36 +/- 14 ml/min (mean +/- SD). There was an increase in the excretion of all amino acids that could be detected in the urine. The renal clearances of urea and creatinine was reduced in some of the patients. The absence of toxic symptoms is consistent with unchanged serum concentrations of ammonia and glutamate.
BACKGROUND: Until present time, suggested treatments for superficial thrombophlebitis induced by intravenous infusion (TFSI), are of uncertain effectiveness and most of them or empirical and not fully researched. The aim of this report is to study the effectiveness and safety of the topical and oral administration of diclofenac in the treatment of TFSI. PATIENTS AND METHODS: In this prospective study 120 patients both female and male were included. All of them developed TFSI during hospitalization and at the same time they were assigned at random to one of the following groups: G-control (n = 40), without treatment; G-topical (n = 40), diclofenac emulsion gel used in a topical way on the concerned area every 8 hours during 48 hours; G-oral (n = 40), diclofenac 75 mg p.o. every 12 hours during 48 hours. The measurements were done at the moment of diagnosis of TFSI (T0) and 48 hours later (T2). Registries of intensity of TFSI were done by quantifying flushing, tumor, heatness and pain. These data were compared considering the averages of differences registered in T2 with respect to T0. A decrease of intensity of TFSI > or = 30% was considered a positive answer to this treatment. The quantitative variables were studied with ANOVA, Kruskal-Wallis test or general linear model and the qualitative with the chi 2 test with Yates correction. The level of significance used was alpha = 0.05. RESULTS: The averages of differences in the intensity of TFSI that were registered in the groups G-control, G-topical and G-oral in T2 compared to T0 are: -0.12 (4.89), -5.70 (3.13), -4.82 (3.14) (p = 0.000). The favorable answers in G-control, G-topical and G-oral were: 20, 60 and 60%, respectively (p = 0.0001). The adverse reactions in G-topical and G-oral were: headache 9-5 (p = 0.2), epigastric pain 4-17 (p = 0.0009), nausea 6-16 (p = 0.01) and local pruritus 5-2 (p = 0.2). The treatment did not report serious adverse reactions in either of the groups. CONCLUSION: The topical treatment of diclofenac can be recommended as an alternative simple, effective and safe therapy for patients who develop TFSI.
The cardiovascular effects of a continuous intravenous infusion of lisuride plus oral domperidone were studied in 16 fluctuating parkinsonian patients as compared to their usual oral therapy with levodopa plus carbidopa. The study was performed using a 24-h ambulatory recording and an automatic noninvasive device for blood pressure monitoring. During lisuride infusion, a significant increase of systolic blood pressure was observed; however, in three patients, a decrease of systolic-diastolic blood pressure occurred; furthermore, a mild increase of atrial arrhythmias and, in two patients, a short run of atrial fibrillation were noted. Asymptomatic orthostatic hypotension, observed in seven patients during levodopa therapy, disappeared during lisuride infusion. Paradoxical hypertensive effects and disappearance of orthostatic hypotension observed in our patients seem related to the concurrent administration of domperidone.
Intravenous infusion of free fatty acid (FFA) 20 mg.kg-1.min-1 produces pulmonary edema, hypoxemia, hyperventilation and increase in the alveolar surfactant content in rabbits in less than 15 min. We tried to study the role of leukotrienes (LT) and the effects of PGI2 in pulmonary response to FFA. We used Piriprost an inhibitor of LT synthesis or Epoprostenol (Prostacyclin: PGI2) in 4 series of rabbits treated with FFA or its vehicle. Piriprost given as an aerosol (0.1% W/W in THAM) scarcely modified the morphofunctional changes induced by FFA. The only pulmonary effect prevented by Piriprost was the increase in surfactant content (disaturated phosphatidylcholine: DSPC) in broncho-alveolar lavage gluid (BAL). PGI2 administered in a dose of 0.1 micrograms.kg-1.min-1 5 minutes prior to a 15 min infusion of FFA was also unable to prevent most of the effects of FFA on the lung. Only the increase in DSPC in BAL was prevented by PGI2. Some animals received a smaller dose of FFA, because they died earlier. Piriprost, as well as PGI2, shortened the survival time of rabbits treated with FFA. This decrease in the survival rate of animals treated with FFA could account for the lack of increase in DSPC post-FFA. Since other morphofunctional changes induced by FFA were scarcely modified by both Piriprost or PGI2, our results suggest that it is unlikely that either leukotrienes on PGI2 may have a significant effect on pulmonary disturbances induced by FFA.
The two-compartment open model is currently used to assess the glomerular filtration rate (GFR) after a single intravenous injection or a constant rate intravenous infusion. This model needs multiple blood samples from a patient, thus numerous limited sampling models have been so far developed to reduce the number of blood samples. In the present study, the three-, four- and n-compartment closed models have been developed to assess GFR after and during a constant rate intravenous infusion, which include the renal and all possible non-renal elimination pathways. Although more non-renal elimination compartments were included in the modelling, the results show it only leads to the increase in the similar analytical solutions for these compartments and the analytical solution for the blood compartment is the same as that in the two-compartment open model. Theoretically, the developed models can be used to assess GFR with a single blood sample at any sampling time with several urine samples.