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Pharmacokinetics of cyclosporin: influence of rate of constant intravenous infusion in renal transplant patients.

1 The pharmacokinetics of cyclosporin were studied in 12 renal transplant patients. Five patients received a constant rate (7 mg kg-1 day-1) intravenous infusion over 72 h and the remainder received rates of 7, 4 and 10 mg kg-1 day-1, consecutively each for at least 24 h. 2 Plasma, separated at 37 degrees C, was analysed by h.p.l.c. 3 The data were best described by a biexponential model. 4 Following the 72 h infusion, a plateau was reached by 24 h and clearance was 0.60 l h-1 kg-1. 5 Clearance associated with the 10 mg kg-1 day-1 infusion rate (0.43 l h-1 kg-1) was estimated to be lower than that following the 4 and 7 mg kg-1 day-1 rates (0.52 and 0.54 l h-1 kg-1 respectively) but the difference is unlikely to be of clinical significance.

Adult↗

The effect of an oral glucose load on sodium and water excretion after rapid intravenous infusion of 0.9% (w/v) saline.

BACKGROUND & AIMS: Previous studies have suggested that oral or intravenous glucose enhances salt and water retention following a saline load. To test this, we studied the effects of an oral glucose load on urinary sodium and water excretion and serum biochemistry in response to a 2l intravenous infusion of 0.9% saline in normal subjects. METHODS: A crossover study was conducted on six male volunteers. On one occasion, they received 2l 0.9% saline intravenously over 1h. A week later, they were given 100ml 50% dextrose orally prior to the same infusion. Subjects passed urine before start of the infusion. Body weight, haematocrit and serum biochemistry were recorded preinfusion and hourly for 6h. Urine was collected for 6h postinfusion and analysed for sodium, potassium and osmolality. RESULTS: The six subjects had a mean (SE) age of 20.9 (0.4) years and BMI of 22.7 (0.2). Median (IQR) water balance over 6h was 1462 (1005-1650)ml after saline and 1203 (989-1735)ml after glucose and saline (NS). Urinary sodium and potassium excretion on the two occasions over 6h were 76 (69-111) vs 74 (92-174)mmol and 31 (29-40) vs 30 (20-36)mmol, respectively (NS). Using repeated measures testing, there was no significant difference in body weight, haematocrit, serum albumin, sodium, potassium, chloride, osmolality and blood glucose measured at hourly intervals on the two occasions. CONCLUSIONS: In contrast to previous literature, in normal subjects, an additional oral glucose load does not appear to have an effect on urinary sodium excretion or serum biochemistry after a rapid 2l infusion of 0.9% saline. This does not preclude an effect under conditions of prior starvation or injury.

Administration, Oral↗

[Use of prolonged intravenous infusions of cisplatin in patients with malignant neoplasms].

11 patients with generalized forms of cancer received 14 courses of 120-hr non-stop intravenous infusions of 20-30 mg/m2/24 hrs of cis-diamminedichloroplatinum supplied by portable pumps (total dose--80-150 mg/m2). Apparent nausea and vomiting were observed only in 4 out of 14 treatment courses 28%. There was no nephrotoxic effect. Therapeutic effect was established in 6 cases of testicular teratocarcinoma. Complete response was obtained in 1 case and partial remission--in 1 case. The rate of 25 mg/m2/24 hrs (for 120 hrs) should be used in further studies of the effectiveness of intravenous infusions of cis-diamminedichloroplatinum.

Adult↗

The regional brain distribution of the neurosteroids pregnenolone and pregnenolone sulfate following intravenous infusion.

We have studied the distribution of the neurosteroids pregnenolone (Pe) and pregnenolone sulfate (PeS) in seven brain regions, and plasma and fat tissues in male adult rats following the intravenous infusion of 14 mg/kg Pe and 18 mg/kg PeS, respectively. After chromatographic separation of steroid sulfate esters and non-conjugated steroids by solid phase octadecyl C18 columns and celite column chromatographic separation of Pe from cross-reacted steroids, the concentrations of Pe and PeS were determined by radioimmunoassay. We found that both Pe and PeS concentrations were significantly increased in plasma, fat and brain compared to the vehicle controls after i.v. infusion of Pe and PeS. In the controls, Pe concentrations were highly correlated within brain regions and between fat and brain regions. Most correlations were lost after Pe and PeS infusions. The content of Pe and PeS was not uniformly distributed in the brain. The hypothalamus contained the highest level of Pe in controls, Pe-infused and PeS-infused rats (12 +/- 3.1, 3500 +/- 180 and 590 +/- 54 ng/g, respectively). The highest concentration of PeS was detected in the hypothalamus (26 +/- 8.2 ng/g) and striatum (17 +/- 4.1 ng/g) in controls, in the hypothalamus (200 +/- 24 ng/g) after PeS infusion as well as in the hypothalamus and medulla oblongata (57 +/- 9.6 and 55 +/- 7.6 ng/g, respectively) after Pe infusion. This study has yielded evidence that PeS injected i.v. can cross the blood-brain barrier without being hydrolysed to the more lipophilic Pe, and can thus be taken up by the brain.

Analysis of Variance↗

Responses of milk production to the intravenous infusion of amino acids in dairy cows given diets of grass silage and cereal-based supplements.

Three experiments were carried out to examine responses of milk production to the intravenous infusion of amino acids in dairy cows given diets of grass silage and supplements based on barley, with or without added soyabean meal and ranging in crude protein content from 16 to 19% in dry matter. Particular attention was given to histidine, administered alone or in combination with methionine, lysine and tryptophan. Responses of milk protein secretion to infusion of histidine were seen only when the diet contained a supplement of barley alone. When soyabean meal was included, there were no responses of milk production to infusion of any of the infused amino acids. Calculations suggested that, although histidine remained first-limiting when soya was included in the diet, any response to infusion of histidine was blocked by the rapidly emerging deficiency of another amino acid, probably leucine. The results confirm that, for diets based on grass silage and supplements of cereal only, histidine is first-limiting such that increases of milk protein secretion can be obtained in response to infusion of histidine alone. In assessing the practical significance of this finding, it should be remembered that greater responses in the yield of milk protein can probably be obtained by substituting 1 kg of soyabean meal for 1 kg of cereal, which is likely to be an easier and cheaper option.

Amino Acids↗

Grepafloxacin concentration in ocular tissues after intravenous infusion in rabbits with intraocular inflammation.

PURPOSE: To determine the penetration of grepafloxacin into ocular tissues during experimental ocular inflammation. METHODS: 10 albino and 10 pigmented rabbits underwent a continuous intravenous infusion of the drug 24 h after injecting Salmonella typhimurium toxin intravitreously, creating ocular inflammation. The animals were killed and grepafloxacin levels were determined in plasma and ocular tissues using high performance liquid chromatography. RESULTS: Grepafloxacin levels achieved a steady-state plasma concentration of 1.5 microg/ml. The drug diffused more towards vascularized tissues (chorioretina and iris) in both albino and pigmented rabbits with a tissue/serum ratio higher than 1. Grepafloxacin showed more affinity to pigmented tissue, rising levels of 40,000-50,000 ng/g in the chorioretina and iris in pigmented animals. After inflammation, grepafloxacin intraocular penetration increased in albino animals with levels exceeding the minimum inhibitory concentration for the most common ocular pathogens. CONCLUSION: Grepafloxacin intraocular penetration is higher in pigmented tissues. Ocular inflammation increases the drug penetration into the vitreous.

Animals↗

Effects of intravenous infusions of diaspirin cross-linked hemoglobin (DCLHb) on sheep.

The purpose of this study was to compare the cardiopulmonary, hematologic, and immunologic responses of unanesthetized sheep to single, "topload", intravenous infusions of either 10 mL/Kg or 40 mL/Kg of Diaspirin Cross-Linked Hemoglobin, 10 mL/Kg or 40 mL/Kg of a Human Serum Albumin (HSA) solution oncotically adjusted with human serum albumin to approximately match the oncotic pressure of the DCLHb, or 10 mL/Kg of Erythrocyte Hemolysate solution prepared in a manner similar to that commonly described in the literature and referred to as "stroma free hemoglobin". Solutions were infused at a rate of 1 mL/Kg/minute and animals were monitored for 72 hours after infusion. These studies demonstrated that in sheep infusion of either DCLHb or HSA solutions was well tolerated and did not produce a significant increase in plasma C3a levels, an increase in the plasma concentration of thromboxane B2, or unexpected fluid shifts. In contrast, infusion of the Erythrocyte Hemolysate produced a greater than 10-fold increase in plasma C3a concentrations, a greater than 6000-fold increase in plasma TxB2 concentration, significant fluid shifts, and changes in a variety of other parameters consistent with induction of a dramatic inflammatory response. These results indicate that appropriately prepared and purified DCLHb solutions do not elicit an inflammatory reaction in sheep.

Animals↗

Delivery of a novel nitrosourea, MCNU, to the brain tissue in glioma-bearing rats. Intracarotid versus intravenous infusion.

We observed the tissue delivery of a novel water-soluble nitrosourea, 1-(2-chloroethyl)-3-(methyl-alpha-D-glucopyranos-6-yl)-1-nitros our ea (MCNU) in rats bearing experimental brain tumors by conducting autoradiography on all. Prior to this study, the development of a streaming phenomenon was ascertained (and thus finding the optimum velocity for intra-arterial infusion) by 14C-iodoantipyrine (IAP) autoradiography. Furthermore, a single pass extraction value of MCNU was measured. At an arterial infusion rate of 0.2 ml/min., the streaming phenomenon was recognized but the tracer was fairly evenly distributed at a rate of 1.0 ml/min. On the other hand, the single pass extraction value for MCNU was 0.18 +/- 0.036 (mean +/- S.D., n = 3, under pentobarbital anesthesia). It was suggested that MCNU is very unlikely to be transported into the normal rat brain. We conducted 14C-MCNU autoradiography to observe tissue distribution of MCNU following its intra-arterial and intravenous infusions in a brain tumor model using rats. The normal side (the side where no infusions were given) and the cerebral cortex at the side affected by the tumor (the side where the infusion was given) showed hardly any uptake of 14C-MCNU in both the intra-arterial and intravenous infusion groups. The tumorous section was divided into the periphery and the center to measure tissue concentration of the tracer in each section. Compared against the cortical section, the periphery and the center showed significant increases in the concentration (approximately 11 to 15 times and 3 to 7 times, respectively, the figure for the cortical region) for both the intra-arterial and intravenous groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Phase I clinical and pharmacology study of 502U83 given as a 24-h continuous intravenous infusion.

502U83 is an arylmethylaminopropanediol that displays significant antitumor activity in a number of murine and human tumor-model systems. In the present phase I study, a 24-h continuous intravenous infusion of this agent was given every 28 days to patients with advanced or refractory solid tumors. In all, 46 patients received a total of 96 cycles of 502U83 at doses ranging from 25 to 8,000 mg/m2. No significant hematologic, gastrointestinal, or neurologic toxicity was observed. At doses of 2,000 mg/m2 and higher, prolongation of the corrected QT interval on ECG was evident in most patients but was completely reversible, was not associated with arrhythmias, and was not dose-limiting. Dose-limiting pulmonary toxicity characterized by acute onset of dyspnea, severe hypoxemia, interstitial pulmonary edema, and death occurred in three patients treated at the highest dose levels. Plasma concentrations of 502U83 and its metabolites were measured by high-performance liquid chromatography. The 502U83 maximal concentration (Cmax) and area under the concentration-time curve (AUC) were proportional to the delivered dose; however, substantial interpatient variability in total body clearance was noted at all dose levels. Significant conversion of 502U83 to two glucuronide metabolites was detected. Metabolite concentrations were highest in the three patients who succumbed to pulmonary toxicity, although the precise contribution of these metabolites to the observed toxic effects is unknown. In view of the unfavorable clinical profile of QTc prolongation and pulmonary toxicity produced by 502U83, further clinical development of this agent has been suspended.

Adult↗

Continuous intravenous infusion of 5-fluorouracil in the treatment of refractory breast cancer.

Ten patients with metastatic breast cancer refractory to multiple chemotherapeutic regimens as well as hormonal therapy were treated with continuous intravenous infusion of 5-fluorouracil (5-FU) at 200-300 mg/m2/24 h through a Broviac catheter using a Cormed pump. The treatment was continued until toxicity developed and restarted after resolution of the toxicity. Most common dose-limiting toxicities were mucositis and diarrhea. No grade II or worse myelosuppression was documented. All the patients had received 5-FU by bolus injection before entering the study. We observed three partial responses and one improvement, with two patients continued on the study (396+ and 90+ days, respectively). We conclude that continuous infusion of 5-FU is safe and tolerable even by heavily pretreated patients with poor performance status and is not cross-resistant to bolus injection of 5-FU and other chemotherapeutic agents. Our report warrants further investigation.

Adult↗

Renal function during intravenous infusion of urological irrigating fluids in the sheep.

BACKGROUND: Oliguria or anuria is an important sign of the transurethral resection syndrome, but the mechanism is not clear. METHODS: We gave an intravenous infusion of 40 ml/kg of glycine 1.5%, sorbitol 2%-mannitol 1%, and isotonic saline (control) in 6 conscious ewes and studied if irrigating fluids cause acute disturbances of kidney function. RESULTS: Both the electrolyte-free solutions induced an increase in urine flow and persistent hypo-osmolality. The renal clearances of p-aminohippuric acid and inulin as well as the unilateral renal blood flow, which was measured via ultrasonic flow probes, increased in response to infusion of glycine but not to sorbitol-mannitol. After the infusions, the renal clearances decreased transiently to below baseline levels. Hypertonic saline was given after half of the infusions of electrolyte-free irrigating fluid. This treatment redistributed water from the cells to the extracellular fluid, but had no effect on renal function. CONCLUSIONS: We conclude that 2500 ml of electrolyte-free irrigating fluid had no detrimental effects on kidney function in sheep. The changes we observed were essentially the same as after infusion of isotonic saline.

Animals↗

Effect of intravenous infusion of amino acids on pancreatic secretion.

BACKGROUND/AIMS: The effect of intravenous administration of amino acids on exocrine pancreatic secretion is controversial. Since amino acids are used in parenteral nutrition of patients with acute pancreatitis or other pancreatic diseases, it seemed useful to establish whether or not they affect pancreatic secretion. METHODOLOGY: Four patients having an external transduodenal drainage of the main pancreatic duct performed after sphincteroplasty for common bile duct stones were studied. Two of them had undergone a Billroth II gastrectomy in the past. Pancreatic secretion was stimulated with low doses of secretin (0.1 CU/kg/h) and cerulein (10 ng/kg/h); after 75 min of stimulation, when pancreatic secretion was stable, a solution of L-amino acids (Freamine III 8.5%) was infused intravenously at a rate of 150 mL/h, for two hours. The volume of pancreatic secretion, bicarbonate and total protein was measured. RESULTS: The infusion of amino acids did not cause significant changes in pancreatic secretion. However, considering the results individually, they caused a clear increase of pancreatic secretion, mainly of bicarbonates (mean increase of 36%) in the two subjects who had not undergone previous surgical procedures and no increase in the two who had had a Billroth II gastrectomy. CONCLUSIONS: The results suggest that intravenous administration of amino acids stimulates exocrine pancreatic secretion in normal subjects but not in those who underwent previous gastrectomy. This stimulatory effect could be mediated by stimulation of gastric acid. This effect should be taken into consideration when amino acids are used in patients with acute pancreatitis or other pancreatic disorders.

Aged↗

Effect of intravenous infusion of omeprazole and ranitidine on twenty-four-hour intragastric pH in patients with a history of duodenal ulcer.

The effect on intragastric pH of two different dose regimens of continuous intravenous infusion of omeprazole (4 or 8 mg/h after a bolus of 80 mg), and ranitidine (0.25 mg/kg/h after a bolus of 50 mg) was studied in 10 patients with duodenal ulcer disease in symptomatic remission. The pH was monitored over 24-hour periods during fasting in a cross-over, randomised design including a baseline period. With the high omeprazole dose it was possible to maintain a pH > or = 4 in all patients but 1 and 6 of the patients also maintained a pH > or = 6. The lower dose of omeprazole seemed to be somewhat less effective. Continuous infusion of ranitidine was as efficient as the higher omeprazole infusion although with a tendency to decreased pH levels towards the end of the 24-hour period. Thus, in order to obtain consistently high pH levels of 4-6 over a prolonged period a continuous infusion of omeprazole, an 80-mg bolus plus a continuous infusion of 8 mg/h seem to be needed.

Circadian Rhythm↗

Rapid estimation of volume of distribution after a short intravenous infusion and its application to dosing adjustments.

A simple and a rapid method to estimate the apparent volume of distribution of drug after single or during multiple short-term intravenous infusion is proposed. This is based on the back extrapolation to the midpoint of infusion. An equation simpler than one previously reported in the literature is also derived to calculate the maintenance dose for multiple short-term intravenous infusion. In addition, an equation to estimate the "priming dose" for infusion during multiple infusion regimen is also derived. The derivations of the equations are based on a linear one-compartment open model for drug disposition in patients. The prposed method is thought to be adequate for the purpose of rapid individualization of dosage regimens. The simplicity of the method, in particular, the solution by the graphic method for estimation of the apparent volume of distribution, might be specially useful for clinicians not well versed in mathematics in applying clinical pharmacokinetics to drug therapy.

Humans↗

Continuous intravenous infusion of high-dose recombinant interleukin-2 for acute myeloid leukaemia--a phase II study.

A group of 13 patients with acute myeloid leukaemia of differing disease status were treated with continuous intravenous infusion of high-dose recombinant interleukin-2 (rIL-2). There was up-regulation of the cellular cytotoxic functions in all these patients following the rIL-2 therapy, with increase in the natural killer (NK) activity, lectin-dependent cellular cytotoxicity, induction of cytotoxicity-linked cytoplasmic serine esterase and lymphocyte activation. However, the clinical response to rIL-2 in these patients was disappointing, especially in patients treated in frank relapse. Although 1 patient treated in early second relapse achieved a third complete remission, the duration of the remission was brief and lasted only 6 months. Adverse reactions among these patients were common. Whether or not lymphokine-activated killer cells are needed to improve the response rate over rIL-2 alone in these patients deserves further investigation.

Adult↗

Continuous intravenous infusion of morphine for severe dyspnea.

We describe eight patients who had terminal lung cancer causing severe dyspnea unrelieved by oxygen, nonnarcotic drugs, or intermittent bolus narcotics. We treated these patients with continuous intravenous infusion of morphine, beginning with bolus IV injections of 1 or 2 mg of morphine every 5 to 10 minutes until the patient reported relief. A continuous morphine infusion was then started, with the hourly dose equal to 50% of the cumulative bolus dose. Vital signs, degree of sedation, and blood gases were serially followed. Six patients achieved good dyspnea relief, one had moderate relief, and one had a poor response. Variable changes were noted in the PaO2, whereas PaCO2 steadily increased in five of seven patients, and pH decreased in six. There was little change in systolic blood pressure or pulse, and only one individual had less than 10 respirations per minute. The major side effect of treatment was sedation, treated by temporarily discontinuing morphine until the patients' mental status improved and then restarting the infusion at a 50% lower hourly morphine dose. Mean time of study was 30 hours (range 16 to 87 hours). Seven of the eight study patients died during treatment. Whether morphine therapy shortened survival is uncertain. We conclude that continuous morphine infusion is effective therapy for severe dyspnea. The treatment is ethically justified. Relief of suffering is the primary goal of therapy, and less risky treatments are unavailable.

Aged↗

Power spectral analysis of the electroencephalographic and hemodynamic correlates of propofol anesthesia in the rat: intravenous infusion.

Based on the tail-flick response to noxious thermal stimuli, we determined in the present study that effective antinociception could be achieved in adult male Sprague-Dawley rats 15 min after intravenous infusion of propofol at 60 mg/kg/h. Simultaneous power spectral analysis of the electroencephalographic (EEG) and systemic arterial pressure signals further revealed a concomitant depression of the activity of all EEG frequency bands (delta, theta, alpha, beta), alongside hypotension, negative inotropic and chronotropic actions, and attenuated baroreceptor reflex and vasomotor activity. These effects were congruent with a plasma concentration of propofol in the arterial blood of 1.70 +/- 0.13 micrograms/ml, as determined by high-performance liquid chromatography.

Anesthesia↗

Intravenous infusion of irrigating fluids containing glycine or mannitol with and without ethanol.

Irrigating fluids consisting of 5% mannitol, 3% mannitol + 1% ethanol, 2.2% glycine and 1.5% glycine + 1% ethanol in water were given by intravenous infusion to seven healthy volunteers at a constant rate of 50 ml./min. over 20 min. The irrigants containing glycine produced hyperkalemia and usually prickling and burning skin sensations and slight nausea. The severity of the symptoms apparently correlated to the blood ammonia level, which increased significantly after the glycine but not after the mannitol infusions. With 5% mannitol, there was a pronounced transient increase of the blood volume and a prolonged hyponatremia. There were no differences between the irrigants in respect to their effects on blood pressure and urine excretion. Ethanol caused no adverse effects and allowed the fluid supplementation to be followed by expired breath tests.

Adult↗