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Ceftazidime in acute myeloid leukemia patients with febrile neutropenia: helpfulness of continuous intravenous infusion in maximizing pharmacodynamic exposure.

The pharmacokinetic-pharmacodynamic profile of a fixed 6-g daily continuous intravenous infusion of ceftazidime was assessed in 20 febrile neutropenic patients with acute myeloid leukemia. Mean steady-state ceftazidime concentrations averaging 40 mg/liter from day 2 on ensured maximized pharmacodynamic exposure (values close to four to five times the MIC breakpoint against Pseudomonas aeruginosa). However, large intra- and interindividual pharmacokinetic variability was documented throughout the study period.

Adult↗

Hematopoietic effects of continuous intravenous infusion of mice with growth factors produced by the WEHI-3 cell line.

A method for continuous intravenous infusion of unanesthetized adult C3H/HeJ or Wx/Wv anemic mice was designed using cage immobilization and a tail vein catheter connected to a model 940 Harvard infusion pump. Infusates included: WEHI-3 cell line dialyzed, 5 times concentrated conditioned medium containing multi-colony-stimulating factor (C-SF) interleukin 3 (IL-3); purified murine IL-3; bacterial endotoxin; serum-free medium, or normal saline. Mice were monitored at days 5-7 after infusion for complete peripheral blood counts and production of granulocytes in vitro by explanted marrow in long-term bone marrow cultures. We observed a stimulatory effect of WEHI-3 conditioned medium infusion that was not attributable to endotoxin and produced significant increases in peripheral blood WBC count and neutrophils, colony-forming units in spleen and numbers of granulocyte/macrophage colony-forming unit culture responsive to both C-SF-1 (L cell C-SF) and multi-C-SF in vitro. This infusion method should prove valuable for test of the in vivo effects of purified growth factors and molecularly cloned hematopoietins.

Animals↗

Conservative treatment of external pancreatic fistulas with parenteral nutrition alone or in combination with continuous intravenous infusion of somatostatin, glucagon or calcitonin.

Treatment with total parenteral nutrition (TPN) alone or combined with continuous intravenous infusion of either somatostatin or calcitonin or glucagon have been carried out upon 45 patients with a high output external pancreatic fistula. No significant difference among these treatment schedules was observed in the percentage of closure of fistulas (85 to 100 per cent of the patients), but patients treated with TPN plus somatostatin had the fistulas close within a significantly (p = 0.000028) shorter period of time. Moreover, this treatment was associated with the strongest inhibition of the output from the fistula (minus 82.3 per cent). Since treatment with somatostatin was not accompanied by any side effect, was followed by a quite rapid closure of the fistulas and allowed an estimated economic savings of about $2,100.00 dollars per patient, it seems to be advisable in the conservative treatment of external pancreatic fistulas.

Calcitonin↗

The pharmacokinetics of anti-thymocyte globulin (ATG) following intravenous infusion in man.

The pharmacokinetics of the distribution and elimination of polyclonal rabbit antithymocyte globulin (ATG) following intravenous infusion was studied in patients who had received renal allografts. ATG concentration was measured using a new enzyme-linked immunoabsorbent assay (ELISA) for the Fc portion of rabbit IgG. Eleven patients received 14 courses of ATG supplied either by Fresenius (F-ATG) or Merieux (M-ATG) as a daily infusion of 2-6 mg/kg body weight for a therapeutic course lasting 5-10 days. The washout phase of ATG elimination was analysed over 0-300 days; results were well-fitted by a single exponential decay (r2 > 0.95) giving a mean elimination half-life (t0.5e) of 29.8 days (range 14.3-45.0, n = 9). Data for the first 4 days of treatment were analysed with linear regression to obtain a mean value for the apparent volume of distribution of ATG (Vd) of 0.12 l/kg body weight (range 0.07 to 0.17, n = 5). These results demonstrate that rabbit ATG has a long half-life in human plasma and an apparent volume of distribution of about twice plasma volume. The relationship between the concentration of ATG measured by this Fc receptor assay and its biological activity requires further study.

Animals↗

[Analysis of population pharmacokinetics with NONMEM in clinical patients treated with amikacin by intravenous infusion].

Clinical data (n = 275) collected from 52 patients with respiratory tract infection receiving amikacin (AMK) by intravenous infusion were analysed with NONMEM, a computer program designed for estimating population pharmacokinetic parameters. Concentrations of AMK in serum were determined by fluorescence polarization immunoassay (FPIA). A two compartment open model was used for analysing AMK population pharmacokinetics. The influence of body weight (BW), creatinine clearance (CC), administration history (HIS) and state of pathology (chronic obstructional pulmonary disease, COPD) on pharmacokinetics was investigated. The pharmacokinetic parameters of AMK were shown to be influenced by creatinine clearance (CC) and COPD.

Adult↗

[Plasma levels of isosorbide dinitrate and its metabolites during intravenous infusion in surgical patients--effect of preoperative administration of isosorbide dinitrate].

Nineteen patients with ischemic heart disease were studied to determine plasma levels of isosorbide dinitrate (ISDN) and its metabolites, isosorbide-2-mononitrate (2-ISMN) and isosorbide-5-mononitrate (5-ISMN) for 6 hrs during intravenous administration of ISDN, using gas chromatography. Differences in plasma levels of these substances were also evaluated in patients with or without preanesthetic medication of ISDN. These patients ranging in ages from 42 to 80 years were administered ISDN intravenously at a rate of 1 micrograms.kg-1 x min-1 during anesthesia and surgery. Preanesthetic administration of ISDN consisted of transdermal application of 40 mg dose. Surgery included gastrectomy, pneumonectomy, extended cholecystectomy, radical mastectomy and so on under either enflurane anesthesia or neuroleptanesthesia. Plasma ISDN levels increased and reached a plateau 3 hrs after the start of intravenous infusion of ISDN in patients of both groups. Plasma 2-ISMN levels increased gradually and reached a plateau 5 hrs after the commencement of intravenous administration of ISDN in patients of both groups. Plasma 5-ISMN levels increased gradually reaching the peak 6 hrs after the start of intravenous infusion of ISDN in both groups. Plasma ISDN, 2-ISMN and 5-ISMN levels were slightly higher in patients who received preanesthetic ISDN than in those who did not receive preanesthetic ISDN. However, there were no statistical differences in plasma ISDN or 2-ISMN levels between the groups except prior to the infusion. On the contrary, plasma 5-ISMN levels were significantly higher in patients who received preanesthetic ISDN than in those who did not receive preanesthetic ISDN for 3 hrs after the start of the infusion.

Adult↗

Efficacy of intravenous infusion of prostacyclin (PGI2) or prostaglandin E1 (PGE1) in augmentation of skin flap blood flow and viability in the pig.

The dose-response effects of 6-h intravenous infusion of PGI2 (0, 5, 10, 25 or 75 ng/kg/min) or PGE1 (0, 25, 50, 100 or 300 ng/kg/min) on skin hemodynamics and viability were studied in 4 x 10 cm random pattern skin flaps (n = 24) raised on both flanks of the pig. Infusion of PGI2 or PGE1 was started immediately after intravenous injection of a loading dose 30 min before skin flap surgery. PGI2 infusion significantly (P less than 0.05) increased the total skin flap capillary blood flow at the dose of 10 ng/kg/min, compared with the control. However, the distance of blood flow along the skin flap from the pedicle to the distal end, i.e. perfusion distance, was not increased. Consequently, the length and area of skin flap viability was also not significantly increased. The effect of PGI2 infusion on skin blood flow was biphasic. Specifically, higher doses (greater than or equal to 25 ng/kg/min) of intravenous PGI2 infusion produced no beneficial effect on the skin flap capillary blood flow. PGI2 infusion at the dose of 10 or 75 ng/kg/min did not significantly increase plasma renin activities or plasma levels of norepinephrine compared with the control, therefore the biphasic effect of PGI2 on skin flap blood flow was not related to circulating levels of norepinephrine or angiotensin. Intravenous infusion of PGE1 did not produce any therapeutic effect on the skin capillary blood flow in the random pattern skin flaps at all doses tested. At the dose of 300 ng/kg/min, the mean arterial blood pressure was 17% lower (P less than 0.05) than the control, but the skin capillary flow still remained similar to the control. It was concluded that intravenous infusion of PGI2 or PGE1 was not effective in augmentation of distal perfusion or length of skin viability in the porcine random pattern skin flaps. Drug treatment modalities for prevention or treatment of skin flap ischemia is discussed.

Alprostadil↗

Effect of intravenous infusion of atriopeptin 3 on immediate renal allograft function.

Thirty-eight recipients of nineteen pairs of cadaveric kidneys were entered into a double-blind randomized study in which one recipient received a 12-hour intravenous infusion of Atriopeptin III (AP-3), a synthetic analogue of atrial natriuretic factor, commencing at release of the vascular clamps, and the other received a placebo infusion. In an initial dose ranging study, successive groups of six kidneys (3 pairs) were randomized to receive each of 0.0125, 0.025, 0.05 micrograms/kg/min AP-3 or placebo. Thereafter 20 kidneys (10 pairs) received 0.1 micrograms/kg/min or placebo. There was no discernable effect of AP-3 on allograft creatinine clearance or sodium excretion either when the highest dose of AP-3 was considered alone or when all doses were considered together. Averaged creatinine clearance over the period 0 to 24 hours after transplantation was 20.1 +/- 14.7 ml/min in patients receiving active treatment and 18.2 +/- 13.7 ml/min in those receiving placebo. Thus, despite the documentation of a protective effect of atrial natriuretic factor in animal models of renal ischemia, it is unlikely that intravenous infusion of AP-3 in this dose range will be of benefit in improving immediate renal allograft graft function.

Atrial Natriuretic Factor↗

Comparison between L-dopa and lisuride intravenous infusions: a clinical study.

L-Dopa is still the most effective drug for the treatment of Parkinson's Disease, but after 5 years or more of therapy fluctuations in motor performance and abnormal involuntary movements commonly appear. Continuous intravenous infusions of L-Dopa abolish or strikingly reduce such fluctuations. Unfortunately, this is not suitable for daily treatment because of the low solubility of L-Dopa. Lisuride is a potent dopamine agonist and is very soluble in water. In this study the clinical effects of L-Dopa and lisuride continuous intravenous infusions were compared in a group of 20 fluctuating parkinsonian patients. L-Dopa controlled fluctuations in almost all the subjects, whereas only seven patients were continuously mobile while taking lisuride. Another seven patients showed a fluctuating response and the remaining six did not satisfactorily respond to lisuride. Dyskinesias were present in all patients during "on" phases, with both levodopa and lisuride treatment.

Adult↗

Continuous intravenous infusion in athymic (nude) rats: an animal model for evaluating the efficacy of anti-cancer agents.

The athymic (nude) rat (rnu/rnu) has been used for a number of years in research into various human tumours involving xenotransplantation. We now report the validation of a continuous intravenous infusion method in nude rats using a tail cuff tether, which enables the study of the efficacy of novel anti-cancer materials in this mutant strain, using intravenous infusion and with no restriction of the animals or of the tumour implantation sites by jackets. Ten animals each had a cannula surgically implanted into the vena cava via the femoral vein and exteriorized via a tail cuff. Animals were housed singly in conventional cages following surgery. Following a recovery period of 5 days all animals were continuously infused with physiological saline at an infusion rate of 0.5 ml/h for a further 37 days. Body weights and food consumption were recorded weekly. Blood samples were taken approximately 14 days post-surgery and analysed for haematology and clinical chemistry parameters. All animals were successfully cannulated, and no unexpected adverse clinical signs were noted during the recovery period and the 37 days of infusion. The results demonstrate that it is possible to surgically cannulate the femoral vein of athymic (nude) rats and infuse them in conventional cages for a period of up to 37 days with minimal adverse effects. The minimal restraint required provides benefits both to the animal and to the conduct of studies such as assessment of tumour growth in the absence of a jacket. Recent work has demonstrated that the same techniques can be successfully applied to the nude mouse.

Animals↗

Intravenous infusions of nifedipine: an alternative for the prevention of hypertension in eye surgery under local anesthesia.

In order to control critical rises of blood pressure during the peri-operative period in elderly hypertensive patients, the effectiveness of a continuous intravenous infusion of nifedipine was studied. In a double blind study, patients (n = 60) who underwent eye surgery under local anesthesia were divided randomly into three groups. Patients who were found to have 200 > SBP > 160 and 120 > DBP > 90 mmHg as the previous day of surgery, as well as patients who did not receive any anti-hypertensive treatment regimen during the last week before surgery, were selected. Five min before performing local anesthesia, a continuous infusion of nifedipine at two different rates of 0.65 mg/h and 1.25 mg/h, was administered in groups A and B respectively, whereas group C received a placebo. SBP, DBP and HR were recorded every 5 min. for an hour. Statistically significant differences among the profiles of the three groups were found. The control group had a higher SBP/DBP. None of the groups, showed significant changes in HR. In conclusion, the intravenous infusion of nifedipine in a dose 1.25 mg/h, seems to control the hypertensive phases of blood pressure, without dropping to any unduly low level, risking undesirable side effects in elderly hypertensive patients during perioperative period.

Aged↗

Gastrointestinal motility and gastric secretion during intravenous infusions of gastrin II.

The effect of intravenous infusion of gastrin II on gastric and colonic motor activity was studied in 12 patients; gastric acid output was also measured. Administration of gastrin at near-maximal dose levels stimulates the motor activity of the antrum but has no measurable effect on the activity of the proximal colon, sigmoid, or rectum. The results suggest that gastrin plays a part in the regulation of gastric motility but that it is not a mediator of the gastro-colic reflex.

Colon↗

Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma.

We examined the feasibility of achieving a rapid response in patients with previously untreated multiple myeloma by administering vincristine 0.4 mg and doxorubicin 9 mg/m2 as a rapid intravenous infusion for 4 d together with intermittent high-dose dexamethasone 40 mg (VAD) for remission induction treatment in patients who were scheduled to receive high-dose therapy. 139 patients (86 male, 53 female; median age 53 years, range 32-65 years; Durie & Salmon stage IIA: 42, IIB: one, IIIA: 89, IIIB: seven) were included in a prospective multicentre study in which VAD was administered as remission induction treatment and was followed by intensified treatment. The response was evaluated according to the criteria of the Eastern Cooperative Oncology Group (ECOG). The results of treatment were evaluable in 134 patients. Five patients died before evaluation. 86 patients (62%) achieved a partial response (PR) and seven patients (5%) achieved a complete response (CR), which equates to a response rate of 67%. The main side-effect was mild neurotoxicity, which was observed in 18% of the patients. Fever or infections were reported in 27% of the patients. VAD administered as an outpatient regimen, based on rapid intravenous infusion, is an effective induction regimen for untreated myeloma with a 67% response rate and acceptable toxicity.

Adult↗

Peripheral intravenous infusion--another cause of air embolism.

We report an unusual complication of intravenous infusion. A 4-week-old baby developed acute cardiopulmonary distress because of air embolism caused by improper preparation of peripheral intravenous set. The estimated amount of infused air was 12 ml (approximately 3.5 ml/kg). The infant recovered promptly after short supportive treatment.

Embolism, Air↗

Pharmacokinetics of FK506 in liver transplant recipients after continuous intravenous infusion.

The first-dose pharmacokinetics of FK506 was studied in nine orthotopic liver transplant patients receiving continuous intravenous infusion of 0.15 mg/kg/day. Multiple blood samples were obtained during the infusion and plasma FK506 concentrations were measured by enzyme-linked immunosorbent assay. The plasma clearance ranged from 0.47 to 5.8 L/minute, and the half-life ranged from 4.5 hours to 33.1 hours. These results indicate the pharmacokinetics of FK506 to be highly variable between patients. FK506 is extensively distributed outside the plasma compartment. FK506 is extensively metabolized in the body, with less than 1% of the administered dose being excreted in the urine as unchanged FK506. The large variability in FK506 kinetics during the immediate post-operative period is attributed to the variability in the functional status of the liver in the transplant patients. Because of the long half-life of FK506, it takes more than 45 hours to reach steady-state concentrations after continuous infusion. Based on the estimated kinetic parameters, it appears that a combination of a bolus or a rapid infusion of .02 mg/kg with a continuous infusion of 0.05 mg/kg/day will provide and maintain a concentration of more than 2 ng/mL from the beginning of the drug treatment.

Adult↗

A phase I trial of recombinant tumor necrosis factor (rTNF) administered by continuous intravenous infusion in patients with disseminated malignancy.

rTNF was administered to 28 patients with advanced metastatic cancers by continuous intravenous infusion for 5 consecutive days every 2 weeks. The dose levels were 30, 40, 70, 110, 180 and 290 micrograms/M2/day. Groups of 3 patients were started at each successive dose level and then on subsequent courses treated with the next dose level through 4 escalations as tolerated. Tumor types were: colon cancer 14; adenocarcinoma of unknown primary, 2; renal cancer, 2; leiomyosarcoma, 2; lung cancer, 1; prostate cancer, 1; thymona, 1; bladder cancer; 1; parotid, 1; Kaposi's sarcoma 2; ovarian 1. Toxicities included fever and chills (usually within the first 8 hours of infusion), fatigue, headache, decreased performance status, hypotension and CNS. All patients experienced leukopenia and thrombocytopenia within 24 hours or less after start of infusion with return of baseline by 72 hours after rTNF was stopped. The fall in these counts averaged 50% and was not dose related. No major changes in liver or renal function, coagulation or blood lipids were seen. Major dose limiting toxicities were fatigue, confusion, thrombocytopenia, seizures, hypotension and decreased performance status. NK cell activity measured against K562 target cells was augmented from about 30% target cell lysis to about 70% target cell lysis over the first 7 days of treatment. Two patients, both with metastatic colon cancer showed transient, objective tumor regression which did not qualify as a partial response. One patient with ovarian cancer had a stable partial response but progressed after 13 courses of treatment. Continuous infusion of TNF can be safely administered to patients with a maximum tolerated dose of only between 30 and 40 micrograms/M2/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytotoxicity Tests, Immunologic↗

A simple intravenous infusion method in rodents for determining the potency of anticonvulsants acting through GABAergic mechanisms.

A simple method of intravenous infusion of convulsant drugs (pentetrazol and bicuculline) into the tail vein of rats has been used to determine seizure threshold and construct log-dose seizure threshold response curves for several anticonvulsant drugs (diazepam, phenobarbitone, pentobarbitone, chlormethiazole and valproate). It has been shown that an index of the dose required to increase seizure threshold by 50% (TI50) can be obtained using small numbers of animals. The advantages of this method over that of the subcutaneous pentetrazol method are several: small numbers of animals required, speed and reproducibility. The data also demonstrate the concordance between TI50 values obtained using pentetrazol and bicuculline as the convulsant agent. It is suggested that this method can be used routinely in screens of anticonvulsant drugs thought to work through GABAergic mechanisms.

Animals↗

Effects of intravenous infusion of 17 amino acids on the secretion of GH, glucagon, and insulin in sheep.

The effects of intravenous infusion of 17 amino acids, each at a dose of 3 mmol/kg over 30 min, on the secretion of insulin, glucagon, and growth hormone (GH) were studied in 6 castrated male sheep. Insulin-like growth factor I (IGF-I) secretion was also studied using eight of the amino acids. Plasma alpha-amino nitrogen reached a peak at 30 min followed by a gradual decrease thereafter. The greatest increase was obtained using aspartic acid and the smallest with methionine, responses to the remaining amino acids lying between these two. Leucine was the most effective amino acid in stimulating insulin secretion but did not produce any increase in glucagon and GH secretion. Alanine, glycine, and serine induced a greater enhancement of both glucagon and insulin secretion than other amino acids. No amino acid was able to specifically stimulate glucagon secretion without also increasing insulin or GH secretion. With regard to insulin and glucagon secretion, amino acids could be divided into groups according to their R groups. Neutral straight-chain amino acids stimulated both insulin and glucagon secretion, with a greater secretory response to shorter C-chain amino acids. Branched-chain amino acids tended to enhance insulin and suppress glucagon secretion. Acidic amino acids caused an increase in GH secretion. Aspartic acid caused the strongest stimulation of GH secretion, exceeding that induced by arginine. No changes in plasma IGF-I were brought about by any of the amino acids tested.

Amino Acids↗